Get 20M+ Full-Text Papers For Less Than $1.50/day. Subscribe now for You or Your Team.

Learn More →

Monocytes and Macrophages in Pregnancy and Pre-Eclampsia

Monocytes and Macrophages in Pregnancy and Pre-Eclampsia REVIEW ARTICLE published: 30 June 2014 doi: 10.3389/fimmu.2014.00298 Monocytes and macrophages in pregnancy and pre-eclampsia Marijke M. Faas*, Floor Spaans and Paul De Vos Immunoendocrinology, Department of Pathology and Medical Biology, Division of Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands Edited by: Preeclampsia is an important complication in pregnancy, characterized by hypertension Sinuhe Hahn, University Hospital and proteinuria in the second half of pregnancy. Generalized activation of the inflamma- Basel, Switzerland tory response is thought to play a role in the pathogenesis of pre-eclampsia. Monocytes Reviewed by: may play a central role in this inflammatory response. Monocytes are short lived cells Juan Carlos Salazar, Connecticut Children’s Medical Center, USA that mature in the circulation and invade into tissues upon an inflammatory stimulus and Fulvio D’Acquisto, Queen Mary develop into macrophages. Macrophages are abundantly present in the endometrium and University of London, UK play a role in implantation and placentation in normal pregnancy. In pre-eclampsia, these *Correspondence: macrophages appear to be present in larger numbers and are also activated. In the present Marijke M. Faas, review, we focused on the role of monocytes and macrophages in the pathophysiology of Immunoendocrinology, Department pre-eclampsia. of Pathology and Medical Biology, Division of Medical Biology, Keywords: pregnancy, pre-eclampsia, monocytes, macrophages, decidua, placenta University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen 7913 GZ, Netherlands e-mail: m.m.faas@umcg.nl INTRODUCTION conditions, may lead to a better understating of the inflammatory Preeclampsia is one of the leading complications of pregnancy, response in normal pregnancy and in pre-eclampsia. Therefore, characterized by hypertension and proteinuria and developing in the present paper will review the systemic and local changes in the second half of pregnancy (1, 2). Preeclampsia is suggested to the decidua in monocytes and macrophages and their subsets dur- be a two stage disease: the first stage being poor placentation (3). ing healthy human pregnancy and pre-eclampsia. Examples from The second stage is the production of pro-inflammatory factors by animal models will also be included. the diseased placenta, which activates the systemic inflammatory response, leading to the signs of pre-eclampsia (3). MONOCYTES AND MACROPHAGES AND THEIR SUBSETS MONOCYTES During normal pregnancy, the circulation of peripheral blood through the placenta results in direct or indirect contact of mater- Monocytes arise from precursors in the bone marrow and com- prise about 5–10% of the circulating blood leukocytes. They cir- nal immune cells with the placenta. This may activate circulating immune cells, especially monocytes (4, 5). In pre-eclampsia, due to culate in the blood for a few days before migrating into tissues to become macrophages or dendritic cells (12). They have important production of pro-inflammatory factors from the placenta (6–9), monocytes are even further activated and together with activation functions in homeostasis, tissue repair, and inflammation (12). It has recently become clear that circulating monocytes are a hetero- of other inflammatory cells, such as granulocytes and endothelial cells, finally induce the full blown syndrome of pre-eclampsia (3). geneous population (12). In humans, the monocyte subsets can be At the maternal–fetal interface, from the beginning of a healthy distinguished based on the expression of CD14, the lipopolysac- charide (LPS) receptor. The main subset (comprising about 90– pregnancy, there is an increase of innate immune cells, such as macrophages and NK cells (10). These macrophages and NK cells 95% of the monocytes) is a subset expressing high levels of CD14, but lacking CD16 (FcgR-III) expression. Since this is the main sub- may have a local immune function, however, they also appear to be important for placental development by promoting trophoblast sets and until recently thought to be the only subset, this subset is usually called “classical subset”. The second subset of monocytes recruitment, spiral artery remodeling, and angiogenesis (11). The present review will focus on macrophages at the maternal–fetal is characterized by low expression of CD14 together with CD16. This subset is often called the non-classical subset. More recently, interface. In normal pregnancy, most of the macrophages at the maternal–fetal interface are M2 macrophages, i.e., immunomod- a third, intermediate subset of monocytes has been defined, called the intermediate subset (13). This subset is characterized by high ulatory macrophages (11). In pre-eclampsia, there appear to be increased numbers of M1 macrophages, suggesting a role for these expression of CD14 in combination with expression of CD16 and macrophages in the poor placental development in pre-eclampsia. is a separate subset of monocytes. It has been suggested that classi- Monocytes and macrophages may thus play an important cal monocytes arise from the bone marrow and mature into non- role in healthy pregnancy as well in the pathophysiology of pre- classical monocytes via intermediate monocytes (13, 14). These subsets differ in many respects, including expression of adhesion eclampsia. Further insight into the role of these cells in these www.frontiersin.org June 2014 | Volume 5 | Article 298 | 1 Faas et al. Monocytes and macrophages in pregnancy and pre-eclampsia molecules and chemokine receptors and function [reviewed in Ref. changes in regulatory T cells (26, 27) and Th17 cells (27). It has (12, 13)]. Classical monocytes are professional phagocytes that been suggested, that to compensate for such changes in the specific can generate reactive oxygen species (ROS) and produce cytokines immune response, also the innate immune response has to adapt to in response to toll-like receptor dependent activation by f.i. LPS. pregnancy. This has most often been shown by increased numbers Non-classical monocytes are weak phagocytes and do not gener- of circulating monocytes and granulocytes, resulting in increased ate ROS, but are more efficient producers of pro-inflammatory number of total leukocytes during pregnancy (28–30). Here, we cytokines after TLR dependent activation (12). This subset has will discuss changes in monocytes during healthy pregnancy and been shown to have a longer half-life and localize to both rest- in pre-eclampsia. ing and inflamed tissue (12). They crawl on the luminal side Although it has been known for a long time that leukocyte of the endothelium and survey endothelial cells and tissues for numbers increase during pregnancy, at that time this was not rec- damage and infection (13). Upon damage or infection, they may ognized as a sign of generalized inflammation in pregnant women. rapidly invade the tissue and initiate the inflammatory response With the introduction of new techniques, most importantly, flow (15). Non-classical monocytes have been shown to be increased in cytometry, function and activation status of leukocytes monocyte various inflammatory diseases (13, 16, 17). could be examined by measuring expression of markers of acti- vation and production of intracellular cytokines. Moreover, the MACROPHAGES flow cytometric analysis did not require isolation of cells from Macrophages are located in all body tissues, where they are impor- whole blood, as measurements could be done in whole blood. tant in detecting, ingesting, and processing foreign material, dead This represents the in vivo situation much better, since isolation cells, and other debris (12). Monocytes are macrophage precursors of leukocytes from blood may activate these cells (31). Using (12); monocytes can be recruited into tissues, to replenish steady the whole blood method, Sacks et al. (32) showed phenotypical state macrophages or can be recruited in inflammatory conditions activation of monocytes during pregnancy, by showing increased (12), where they mature into macrophages (or dendritic cells) expression of the activation markers CD11b, CD14, and CD64 on (12). Macrophages play an important role in the innate and adap- monocytes from pregnant women as compared with monocytes tive immune responses to pathogens and are important mediators from non-pregnant women. Afterward, these results have been of inflammatory processes (12). However, they also have anti- confirmed by others (33–35). inflammatory properties, as they are also involved in the resolution The monocytes are also functionally changed in pregnant of the inflammation (12). Indeed, several macrophage subsets with women. This has, for instance, been demonstrated by measuring distinct functions have been described. Broadly, they can be clas- the production of oxygen free radicals (32), which is increased in sified into two groups: M1 or classically activated macrophages, pregnant women. Although some authors have shown increased and M2 or alternatively activated macrophages (18). These sub- cytokine production by non-stimulated monocytes from pregnant sets differ in receptor, cytokine, and chemokine expression and women vs. non-pregnant women (34), others could not confirm in effector function (18). M1 macrophages are microbicidal and this finding and only observed cytokine production by stimulated inflammatory, M2 macrophages are immunomodulatory, which monocytes (8, 30). Whether stimulated cytokine production of can induce tolerance and the resolution of inflammation, and pregnant monocytes is increased or decreased as compared to are only weak microbicidal (18). It has been suggested that these non-pregnant women seems to depend on the stimulus. After two populations may be extreme ends of polarization and that stimulation with only LPS cytokine production by monocytes macrophages may actively switch their phenotype, depending on from pregnant women was decreased as compared with cytokine the environment (19). production by monocytes from non-pregnant women (30, 36, 37). There is debate on the fate of the different monocyte subsets; it However, after stimulation of monocytes with both LPS and IFNg, is unclear whether tissue macrophages are derived from a specific monocytes of pregnant women showed increased cytokine pro- monocyte subset or from either subset randomly (12). It has been duction as compared with monocytes from non-pregnant women suggested that classical monocytes preferentially differentiate into (38). Although these findings seem contradictory, they can be M1 macrophages, while the non-classical monocytes preferentially explained as follows: decreased cytokine production of mono- differentiate into M2 macrophages during inflammation (20). cytes from pregnant women following LPS stimulation is a sign However, various studies have shown that such a strict distinction of activation of monocytes, since activated monocytes become between differentiation of classical and non-classical monocytes tolerant to LPS (39). IFNg, however, abrogates LPS tolerance may not be very likely and that it may depend on the model and (40). Therefore, if LPS tolerance is abrogated by IFNg during the inflammatory stimulus whether a monocyte differentiates into pregnancy, monocytes produce increased amounts of cytokines an M1 or M2 macrophage (20, 21). during pregnancy. The above mentioned studies have been per- formed in the third trimester of pregnancy and based on all MONOCYTES IN PREGNANCY above mentioned data, it is now generally accepted that mono- During normal pregnancy, the female immune system has to adapt cytes are activated during pregnancy. However, little is known to the presence of the semi-allogeneic fetus. Many changes in the about monocyte activation during the course of pregnancy. How- peripheral circulation have been observed, both in the specific ever, gradually developing monocyte activation may occur during and innate immune response. In the specific immune response, a the course of pregnancy, since one paper showed progressive phe- decreased Th1/Th2 ratio has been observed in both T cells (22–24) notypical activation of monocytes from the first trimester to the as well as in NK cells (23, 25). These changes may be associated with third trimester (34). Frontiers in Immunology | Inflammation June 2014 | Volume 5 | Article 298 | 2 Faas et al. Monocytes and macrophages in pregnancy and pre-eclampsia MONOCYTE SUBSETS IN PREGNANCY Al-ofi et al. included a more heterogeneous group of pre-eclamptic In the studies presented above, monocytes have been characterized women). by CD14 expression, indicating that mainly classical monocytes have been studied in pregnancy. Recently, we conducted a study POSSIBLE MECHANISMS OF MONOCYTE ACTIVATION IN PREGNANCY in which we identified the three subtypes of monocytes in preg- AND PRE-ECLAMPSIA nant women (41). We showed a decreased number of classical The exact mechanisms involved in the activation of monocytes monocytes and an increased number of intermediate monocytes in during pregnancy and pre-eclampsia remain unknown. The most healthy pregnancy. These results are in line with the suggestion that obvious suggestion is that the placenta is involved. Peripheral pregnancy is an inflammatory condition, since in other inflamma- monocytes circulate through the placental circulation and come tory diseases, this intermediate subset has also been shown to be into close contact with the semi-allogeneic villous syncytiotro- increased (42, 43). Our data, however, were not in line with data phoblast (Figure 1). This may activate monocytes. This notion of Al-ofi et al. (44), who showed increased numbers of classical is supported by the fact that monocytes become activated dur- monocytes and decreased numbers of non-classical monocytes in ing their passage through the placenta (5). It is, however, unsure pregnant vs. non-pregnant women. The reason for this difference whether this activation of monocytes occurs due to direct contact, is unclear, but may be due to differences in experimental meth- since several soluble placental products, such as cytokines (57), ods. Further studies are warranted to evaluate whether the subsets placental microparticles (58), fetal DNA (59), released into the respond differently to stimulation in pregnant and non-pregnant maternal circulation, may also activate monocytes (60). women. Many factors may be involved in further activation of mono- cytes during pre-eclampsia. Factors may be derived from the MONOCYTES AND PARTURITION stressed placenta, such as anti-angiogenic factors (61), pla- Parturition is associated with an inflammatory response (45). At cental microparticles (62), or ATP (9), which are released at the end of gestation, the number of leukocytes in the uterine tissue increased amounts from the pre-eclamptic placenta. These fac- are increased (46). Also in the peripheral circulation just before tors may activate the monocytes. Also upregulation of various delivery, further phenotypical activation of monocytes in com- pro-inflammatory cytokines, such as TNFa, IL-1b, IL-18, in the parison with earlier in pregnancy has been shown (47), indicating placenta of pre-eclamptic women has been observed (63–65). On further activation of these cells just before delivery. In line with the other hand, decreased levels of the anti-inflammatory cytokine this suggestion, more recently, Vega-Sanchez et al. (48) showed IL-10 have been observed in the placenta of pre-eclamptic women differences in cytokine production of monocytes between preg- (66, 67). These increased levels of pro-inflammatory cytokines in nant women in labor and pregnant women not in labor. A role the pre-eclamptic placenta may be responsible for the increased for activated monocytes in parturition can also be deduced from data from pre-term labor, where increased expression of activation markers by monocytes has been observed compared with healthy pregnancy (49). MONOCYTES IN PRE-ECLAMPSIA It has now been well-established that during pre-eclampsia, the innate immune system is even further activated as compared with normal pregnancy (50). Activation of monocytes has been demonstrated by increased expression of inflammation associated adhesion molecules such as CD11b, ICAM-1, and CD14 (5, 32, 51, 52). However, monocytes are not only phenotypically activated, they also produced increased amounts of oxygen free radicals as compared to normal pregnancy (32) and their cytokine pro- duction also differed as compared to monocytes from normal pregnant women (38, 53–56). As for normal pregnancy, the above mentioned studies did not take into account the presence of mono- cyte subsets and monocytes are generally defined as CD14 positive. In our recent study, we observed decreased numbers of classical FIGURE 1 | Schematic overview of the placenta. The placenta consists of monocytes and an increased numbers of intermediate monocytes a fetal part and a maternal part. In the fetal part of the placenta, chorionic in women with pre-eclampsia as compared with normal preg- villi, covered with syncytiotrophoblast, bath in maternal blood of the nant women (41). Although Al-ofi et al. also showed decreased intervillous space. Direct or indirect contact (via soluble factors) of numbers of classical monocytes, in contrast to our study, they monocytes with the syncytiotrophoblast may results in monocyte activation. The maternal part of the placenta consists of decidua in which showed increased numbers of non-classical monocytes in pre- remodeled spiral arteries are present, which take maternal blood to the eclamptic women compared with healthy pregnant women (44). intervillous space. In the decidua fetal trophoblast, and maternal As explained above, this may be due to different techniques used, macrophages and NK cells are present and necessary for immune but may also be due to a different selection of patient groups regulation and spiral artery remodeling ©ilusjessy – Fotolia.com. (we exclusively included early onset pre-eclamptic women, while www.frontiersin.org June 2014 | Volume 5 | Article 298 | 3 Faas et al. Monocytes and macrophages in pregnancy and pre-eclampsia circulating levels of these cytokines in pre-eclamptic patients (68, be similar in rat and human pregnancy. Therefore pregnancy- 69). These cytokines may also activate the monocytes. Since mono- induced changes in the immune response may also be similar to cytes themselves are potent producers of cytokines, the activation human pregnancy. Indeed, similar phenotypical and functional of monocyte by placental factors and cytokines may in turn result activation of monocytes during the course of pregnancy have been in a vicious circle of monocytes activation and cytokine pro- observed in rats as compared with humans (75, 76). Moreover, in duction leading to persistent increased monocyte activation in accordance with human pregnancy, we found decreased numbers pre-eclampsia. of classical monocytes and increased numbers of non-classical It appears to be important for induction of pre-eclamptic signs monocytes during pregnancy in this species (41). how monocytes are activated. In pregnant rats, hypertension and Various rat models have suggested that activation of mono- proteinuria can only be induced after infusion with E coli LPS cytes, by LPS, ATP, or TNFa during pregnancy, induced pre- (70), not after infusion of LPS from Porphyromonas gingivalis (71), eclampsia-like signs (70, 77, 78). Interestingly, such pre-eclampsia- despite the fact that monocytes are activated by this LPS (72). like syndromes were only induced in pregnant rats, not in non- This may explain why certain infections, such as urinary tract pregnant rats (70, 77). The pathophysiology of the LPS and ATP infections or periodontitis, may increase the risk of pre-eclampsia, induced pre-eclampsia was characterized by a pregnancy-specific while other infections, such as CMV or malaria do not increase the inflammatory response, characterized by persistent general (75, risk for pre-eclampsia (73). Apparently, the immune response, and 76, 79) and glomerular (79, 80) inflammation, in which mono- specifically monocyte activation is different in different infections. cytes play a major role. In the ATP model, we have shown that, Differences may amongst others relate to differences in cytokine similar to human pre-eclampsia, non-classical monocytes are production between states of monocytes activation, since we have increased and activated by ATP, suggesting an important role previously shown that activation of monocytes with E coli LPS or for this subset in pre-eclampsia. Together, these animal studies P. gingivalis LPS resulted in different cytokine production (36). support the hypothesis that activation of monocytes in preg- nancy may result in pre-eclampsia-like signs, such as hypertension MONOCYTES DURING PREGNANCY AND EXPERIMENTAL and proteinuria. PRE-ECLAMPSIA IN ANIMALS Based on the above data on monocytes during pregnancy and Although it is now generally accepted that during pregnancy pre-eclampsia, we suggest that factors that arise from the healthy monocytes are activated and that they are even further activated placenta during pregnancy induce phenotypical activation of during pre-eclampsia, whether this is the cause or consequence monocytes and induce increased maturation toward non-classical of pre-eclampsia still remains to be shown. It is difficult to study monocytes. These factors may also affect endothelial cells directly the role of monocytes in pregnancy and pre-eclampsia in human (Figure 2A). During pre-eclampsia, the stressed placenta starts subjects. Therefore, animal models are needed. A good animal to produce various pro-inflammatory factors, which further acti- model to study innate immune responses in pregnancy is the vate the monocytes and further increased monocyte maturation rat. Although not completely similar, like humans, rats have a toward non-classical monocytes. Monocyte activation results in hemochorial placenta, showing deep trophoblast invasion into the monocyte cytokine production. Via a vicious circle, these cytokines uterine wall (74) indicating that fetal–maternal interactions may may further activate the monocytes themselves as well as the FIGURE 2 | Schematic overview of the role of monocytes during healthy monocytes toward non-classical monocytes (3). Numbers non-classical pregnancy (A) and pre-eclampsia (B). During healthy pregnancy, placental monocytes are increased and they may play an important role in this factors (1) activate monocytes (2) and may affect endothelial cells (2) and inflammatory process, since they are known to produce increased numbers induce increased maturation of classical monocytes toward non-classical of cytokines upon activation (4). These cytokines further activate the monocytes (3). During pre-eclampsia, more and other soluble factors are monocytes (5) as well as endothelial cells (5). This vicious circle of activation produced from the stressed placenta (1), resulting in further activation of of monocytes and endothelial cells finally results in the symptoms of monocytes and endothelial cells (2) and further maturation of classical pre-eclampsia, such as hypertension and proteinuria. Frontiers in Immunology | Inflammation June 2014 | Volume 5 | Article 298 | 4 Faas et al. Monocytes and macrophages in pregnancy and pre-eclampsia endothelial cells, finally resulting in the signs of pre-eclampsia, Although they express many markers of M2 macrophages, such such as proteinuria and hypertension (Figure 2B). as CD206, CD163, and DC-sign (100–102), they appeared not to be typical M2 macrophages, since they are not induced by Th2 DECIDUAL MACROPHAGES cytokines, such as IL4, but by M-CSF and IL-10 (102). These Macrophages are already present in the non-pregnant data are in line with the abundant presence of M-CSF and IL- endometrium, although in low numbers (81). Since their num- 10 in the decidua (103–105). The M2 phenotype is most likely bers fluctuate during the menstrual cycle (81, 82), it seems likely due to hypermethylation of genes encoding markers of classical that these are under hormonal control (83). After fertilization, the activation and hypomethylation of genes encoding markers for number of uterine macrophages increase, due to expression of non-classical activation (106). Next to the typical M2 cytokine various chemokines (84) and during pregnancy macrophages are gene expression, these decidual macrophages also showed gene abundantly present in the decidua at all times of pregnancy (85). expression for inflammatory cytokines such as IL-6 and TNFa During pregnancy, they comprise about 20–30% of all decidual (102, 107). The production of pro-inflammatory cytokines by leukocytes (86, 87). The number of decidual macrophages may decidual macrophages may also be explained by the presence of vary with gestational age being highest in the first and second two macrophage subpopulations in the early decidua (107). One trimester (88). Macrophages in the decidua are usually associ- of these subsets may be a more pro-inflammatory subset, since this ated with spiral arteries and glands as well as with extravillous subset expressed genes associated with inflammation. The other trophoblast (86, 89), but are also found in the myometrium subset, which was higher in number, expressed genes associated (85). When the presence of macrophages in the decidua was with extracellular matrix formation, networking, communication, first discovered, it was suggested that these cells were recruited and growth (107). as the result of an immune response to the semi-allogeneic fetus Apart from the putative role of M-CSF and IL-10 in induc- (90). However, it is now generally accepted that macrophages, tion of M2 macrophages in the decidua, other factors have also and other immune cells present in the decidua, are necessary been suggested to be involved in inducing/maintaining the M2 for successful implantation (85). Various studies have focused phenotype in decidual macrophages. Decidual macrophages have on specific functions of macrophages in the decidua and it been shown to express inhibitory receptors immunoglobulin like has been suggested that the decidual macrophages have various transcript (ILT)2 and ILT4 (108). These receptors can bind to roles during pregnancy, mainly in placentation (91), but they HLA-G expressed on invading extravillous trophoblast (108), may also play a role in protecting the fetus against intrauterine after which a negative signal is delivered to the macrophages, infection (92). resulting in tolerance to the trophoblast and the induction of anti-inflammatory cytokines. It has also been suggested that the DECIDUAL MACROPHAGES IN EARLY PREGNANCY engulfment of the apoptotic cells induced an immunosuppressive Most of the studies on macrophages in the decidua have been per- and anti-inflammatory phenotype of the macrophages (97). Not formed in early pregnancy. At this time of pregnancy, macrophages only the phagocytosis of apoptotic cells, but also the phagocyto- are located near the spiral arteries during trophoblast invasion and sis of trophoblast cell debris at the maternal–fetal interface may spiral artery remodeling (86, 89). The role of macrophages in spiral be associated with the M2 phenotype of macrophages (109–111). artery remodeling was further emphasized by the fact that they are In addition, as it has been suggested that non-classical mono- present even before the presence of extravillous trophoblast (93). cytes preferentially differentiate into M2 macrophages (20), it At that time, disruption and disorganization of vascular smooth may be speculated that the increased numbers of non-classical muscle cells and endothelial cells was also observed (93). This monocytes in the circulation during pregnancy (41), results in suggests that macrophages may be important in the very early increased invasion of these cells into the decidua to become M2 phases of spiral artery remodeling, preparing the spiral arteries macrophages. for further remodeling by trophoblast cells (93). Their suggested role in vascular remodeling is in accordance with the findings DECIDUAL MACROPHAGES IN LATE PREGNANCY of production of factors associated with angiogenesis and tissue Macrophages are present in the decidua throughout pregnancy remodeling by these cells (94, 95). Indeed macrophages, which until the end of pregnancy, although their numbers may decrease at were MMP 9 positive, and which were shown to have phago- the end of pregnancy (88). The exact role of decidual macrophages cytotic capacities were found to infiltrate spiral arteries during at the end of pregnancy remains to be established, it seems, remodeling (96). Macrophages have also been shown to be impor- however, likely that they are still involved in immunoregu- tant for clearance of apoptotic cells in the decidua (97). Apoptosis lation and clearance of apoptotic cells. Indeed, many of the is an important process during spiral artery remodeling and tro- macrophages present in the decidua at the end of pregnancy, phoblast invasion. During these processes, apoptotic trophoblast appeared to be M2 macrophages (112). The potential protective cells (98) as well apoptotic cells in the vascular wall that is being effect of M2 macrophages for the fetus was recently shown by remodeled have been observed (93). By engulfment of the apop- van Schonkeren et al., who showed the presence of an inflam- totic cells, macrophages prevent the release of pro-inflammatory matory lesion in placentae from women who underwent egg substances from the apoptotic cells into the decidua [reviewed in donation (113). This lesion consisted of maternal cells, express- Ref. (97)]. ing high levels of CD14 and CD163, suggesting the presence Decidual macrophages have mainly been classified as M2- of M2 macrophages. These lesions appeared to protect against like macrophages, i.e., immunomodulatory macrophages (99). pre-eclampsia (113). www.frontiersin.org June 2014 | Volume 5 | Article 298 | 5 Faas et al. Monocytes and macrophages in pregnancy and pre-eclampsia DECIDUAL MACROPHAGES IN PRE-ECLAMPSIA (120, 121). The presence of macrophages in the spiral arteries Preeclampsia is associated with defective trophoblast invasion and may be associated with the development of acute artherosis (120). spiral artery remodeling: while in healthy pregnancy, spiral artery Acute artherosis is a process mainly seen in poorly remodeled spi- remodeling extends into the myometrium, in pre-eclampsia, spiral ral arteries at the end of pregnancy, characterized by the presence artery remodeling can only be found in the decidua (3). Unfor- of subendothelial CD68 positive foam cells (123). Its presence is tunately, not very many studies focused on macrophages in the associated with adverse fetal and maternal outcome (124). decidua in pre-eclampsia. Most of the studies in pre-eclampsia The question remains whether the increased presence of were obviously performed after delivery of the placenta. Some macrophages in the decidua of pre-eclamptic women is the of the studies reported decreased numbers of macrophages in cause or the result of pre-eclampsia. This question is difficult the decidua of pre-eclamptic patients (114, 115). Most of the to answer, due to the difficulties of obtaining material from studies, however, found increased numbers of macrophages in early decidua of women who later in pregnancy developed pre- pre-eclamptic patients (112, 116–118). These data may not neces- eclampsia. However, recently we have shown that in early decidua sarily be conflicting, since not only different methods were used from women who later developed pregnancy-induced hyperten- (Williams and Burk performed a flow cytometric study, while sion (PIH) (including pre-eclampsia) CD68 mRNA expression was the other studies were immunohistochemical studies), also dif- increased (125), suggesting increased numbers of macrophages ferent antibodies were used. Increased numbers of macrophages in the early decidua of women who later develop hyperten- in the decidua of pre-eclamptic patients appears to be in line with sion in pregnancy. Moreover, the CD206/CD68 mRNA ratio increased presence of macrophage chemotactic factors, such as was decreased in PIH women, suggesting that decreased num- M-CSF, IL-8, and MCP-1 (119–121) in pre-eclamptic patients. bers of M2 macrophages are present in the decidua of women Not only numbers of macrophages were found to be different in who later develop pregnancy-induced hypertension (125). The pre-eclamptic patients, macrophages may also be differently acti- increased numbers of macrophages, with decreased numbers of vated in pre-eclampsia (120–122). This may be in line with the M2 macrophages may thus already be present before the onset pre- presence of increased pro-inflammatory cytokines (63–65) and eclampsia and therefore suggest a role for macrophages in defec- decreased anti-inflammatory cytokines in the placenta of pre- tive trophoblast invasion and spiral artery remodeling. Recent eclamptic women (66, 67). More recently, it has been shown that in vitro data showed that macrophages migrate toward invading in the decidua of pre-eclamptic women decreased numbers of M2 trophoblast (126), while other groups have shown that activated macrophages are present (112). Differences in macrophage num- macrophages in vitro are able to inhibit trophoblast invasion and bers may be regional, since increased numbers of macrophages spiral artery remodeling (127, 128). In vivo, data have shown that were found around the spiral arteries of pre-eclamptic patients there is a reciprocal presence of trophoblast cells and macrophages FIGURE 3 | Schematic overview of the role of decidual macrophages in and tissue remodeling (such as MMP and VEGF). They also play a role in pregnancy (A) and pre-eclampsia (B). During normal pregnancy, M2-like immunomodulation, for instance by producing IL-10. During pre-eclampsia, macrophages are present around spiral arteries and play a role in remodeling increased numbers of M1-like macrophages are found. They may produce of these arteries by producing various factors associated with angiogenesis pro-inflammatory cytokines, such as TNFa, IL-1b, or IL-18. Frontiers in Immunology | Inflammation June 2014 | Volume 5 | Article 298 | 6 Faas et al. Monocytes and macrophages in pregnancy and pre-eclampsia in the spiral arteries of both healthy and pre-eclamptic women (121). Therefore the increased numbers of macrophages in and around spiral arteries of pre-eclamptic women (121) may inhibit spiral artery remodeling. Since it is difficult to study the role of macrophages in pre- eclampsia in humans, animal models may help in understanding critical questions. Studying whether trophoblast invasion and spiral artery remodeling is associated with macrophages in ani- mal models for pre-eclampsia may shed light on the question whether increased numbers of macrophages in the decidua are the cause or the result of pre-eclampsia. In an animal model for pre-eclampsia induced by multiple doses of LPS in pregnant rats, decreased trophoblast invasion and spiral artery remodeling after LPS was associated with increased numbers of macrophages. We studied this subject and showed increased invasion of acti- vated macrophages in the mesometrial triangle (the equivalent of the placental bed in humans) before defective trophoblast inva- sion and spiral artery remodeling (129). This appears to be in line with the sparse human data and suggests a role for activated macrophages in the pathophysiology of pre-eclampsia. M2-like macrophages are thus abundantly present in the decidua of healthy pregnant women. They are observed in the presence of spiral arteries and extravillous trophoblast cells and may play a role in spiral artery remodeling by producing factors associated with angiogenesis and tissue remodeling, such as MMPs and VEGF (Figure 3A). During pre-eclampsia, increased num- bers of decidual macrophages are observed, which may be of the M1 phenotype and therefore produce pro-inflammatory cytokines FIGURE 4 | Summary of monocytes and macrophages in (Figure 3B). These activated macrophages may affect spiral arter- pregnancy and pre-eclampsia. In healthy pregnancy, soluble factors ies and may induce acute artherosis, affecting the placental blood from the villous trophoblast activate circulating monocytes, induce circulation. maturation of classical monocytes toward non-classical monocytes and affect endothelial cells. Non-classical monocytes will invade into the decidua to become M2-like macrophages to support healthy SUMMARY placentation and immunomodulation. During pre-eclampsia, decreased Monocytes and macrophages play important roles in pregnancy remodeling of the spiral arteries will results in a stressed placenta, and pre-eclampsia. Monocyte activation and increased numbers which produces increased amounts or different soluble factors as of non-classical monocytes, is important for normal pregnancy. compared with healthy pregnancy. The soluble factors will further Monocyte derived macrophages, especially M2-like macrophages activate the monocytes, induce further maturation of classical monocytes toward non-classical monocytes and activate endothelial (which may be derived from non-classical monocytes) in the cells. Activated monocytes, by f.i. producing cytokines, further affect decidua in healthy pregnancy play an important role in blastocyst monocytes and endothelial cells. This vicious circle of monocyte and implantation, trophoblast invasion, and spiral artery remodeling endothelial cell activation results in the maternal symptoms of as well as in defense against infection and in immunomodula- pre-eclampsia, i.e., hypertension and proteinuria. Moreover, activated tion (Figure 4). During pre-eclampsia, decreased spiral artery classical and non-classical monocytes may invade into the decidua to develop into M1-like and M2-like macrophages, resulting in increased remodeling results in increased production of soluble factors numbers of M1-like macrophages in the pre-eclamptic decidua. The (or different factors), inducing further activation of both classi- M1-like macrophages may affect the spiral arteries resulting in f.i. acute cal and non-classical monocytes and further maturation toward atherosis, thereby further affecting the placental blood circulation. non-classical monocytes. These placental factors as well as the activated monocytes also induce activation of endothelial cells. Activated monocytes (both classical and non-classical monocytes) may invade into the decidua, resulting in increased numbers of decidual macrophages do also play a role in the aberrant spiral M1-like macrophages in the decidua of pre-eclamptic women artery remodeling early in pregnancy. The question thus remains (Figure 4). The M1-like macrophages may affect the spiral arteries, as to what induces the aberrant spiral artery remodeling? Future by for instance inducing acute artherosis. This may further affect studies should therefore not only focus on the three monocyte sub- the placental blood circulation and stress the placenta. sets in pregnancy and pre-eclampsia, but also on the relationship Unfortunately, most studies on monocytes and macrophages between the circulating monocyte subsets and macrophages in the in pre-eclampsia have been performed during pre-eclampsia. decidua. Moreover, since data on macrophages in the decidua in Although we do believe that monocytes and decidual macrophages and before pre-eclampsia are relatively scarce future studies should do play a role in inducing the maternal symptoms of pre- therefore also focus on macrophage function and phenotype in eclampsia, it is relatively unknown whether monocytes and and before pre-eclampsia. www.frontiersin.org June 2014 | Volume 5 | Article 298 | 7 Faas et al. Monocytes and macrophages in pregnancy and pre-eclampsia REFERENCES 23. Veenstra van Nieuwenhoven AL, Bouman A, Moes H, Heineman MJ, de Leij LF, 1. Steegers EA, von Dadelszen P, Duvekot JJ, Pijnenborg R. Pre-eclampsia. Lancet Santema J, et al. Cytokine production in natural killer cells and lymphocytes in (2010) 376(9741):631–44. doi:10.1016/S0140- 6736(10)60279- 6 pregnant women compared with women in the follicular phase of the ovarian 2. Duley L. The global impact of pre-eclampsia and eclampsia. Semin Perinatol cycle. Fertil Steril (2002) 77(5):1032–7. doi:10.1016/S0015- 0282(02)02976- X (2009) 33(3):130–7. doi:10.1053/j.semperi.2009.02.010 24. Saito S, Sakai M, Sasaki Y, Tanebe K, Tsuda H, Michimata T. Quantitative 3. Redman CW, Sargent IL. Placental stress and pre-eclampsia: a revised view. analysis of peripheral blood Th0, Th1, Th2 and the Th1:Th2 cell ratio dur- Placenta (2009) 30(Suppl A):S38–42. doi:10.1016/j.placenta.2008.11.021 ing normal pregnancy and preeclampsia. Clin Exp Immunol (1999) 117:550–5. 4. Sacks GP, Sargent IL, Redman CWG. An innate view of human pregnancy. doi:10.1046/j.1365- 2249.1999.00997.x Immunol Today (1999) 20(3):114–8. doi:10.1016/S0167- 5699(98)01393- 0 25. Borzychowski AM, Croy BA, Chan WL, Redman CW, Sargent IL. Changes in 5. Mellembakken JR, Aukrust P, Olafsen MK, Ueland T, Hestdal K, Videm V. systemic type 1 and type 2 immunity in normal pregnancy and pre-eclampsia Activation of leukocytes during the uteroplacental passage in preeclampsia. may be mediated by natural killer cells. Eur J Immunol (2005) 35(10):3054–63. Hypertension (2002) 39(1):155–60. doi:10.1161/hy0102.100778 doi:10.1002/eji.200425929 6. Hung TH, Charnock-Jones DS, Skepper JN, Burton GJ. Secretion of tumor 26. Ernerudh J, Berg G, Mjösberg J. Regulatory T helper cells in pregnancy and necrosis factor-alpha from human placental tissues induced by hypoxia- their roles in systemic versus local immune tolerance. Am J Reprod Immunol reoxygenation causes endothelial cell activation in vitro: a potential medi- (2011) 66(Suppl 1):31–43. doi:10.1111/j.1600- 0897.2011.01049.x ator of the inflammatory response in preeclampsia. Am J Pathol (2004) 27. Saito S, Nakashima A, Shima T, Ito M. Th1/Th2/Th17 and regulatory T- 164(3):1049–61. doi:10.1016/S0002- 9440(10)63192- 6 cell paradigm in pregnancy. Am J Reprod Immunol (2010) 63(6):601–10. 7. Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, et al. Circu- doi:10.1111/j.1600- 0897.2010.00852.x lating angiogenic factors and the risk of preeclampsia. N Engl J Med (2004) 28. Siegel I, Gleicher N. Changes in peripheral mononuclear cells in pregnancy. 350(7):672–83. doi:10.1056/NEJMoa031884 Am J Reprod Immunol (1981) 1(3):154–5. 8. Germain SJ, Sacks GP, Soorana SR, Sargent IL, Redman CW. Systemic inflam- 29. Kuhnert M, Strohmeier R, Stegmuller M, Halberstadt E. Changes in lympho- matory priming in normal pregnancy and preeclampsia: the role of circu- cyte subsets during normal pregnancy. Obstet Gynecol (1998) 76:147–51. lating syncytiotrophoblast microparticles. J Immunol (2007) 178(9):5949–56. 30. Veenstra van Nieuwenhoven AL, Bouman A, Moes H, Heineman MJ, de Leij doi:10.4049/jimmunol.178.9.5949 FMLH, Santema J, et al. Endotoxin-induced cytokine production of mono- 9. Spaans F, Vos PD, Bakker WW, van Goor H, Faas MM. Danger signals from cytes of third trimester pregnant women compared to women in the follic- ATP and adenosine in pregnancy and preeclampsia. Hypertension (2014) ular phase of the menstrual cycle. Am J Obstet Gynecol (2003) 188:1073–7. 63(6):1154–60. doi:10.1161/HYPERTENSIONAHA.114.03240 doi:10.1067/mob.2003.263 10. Wallace AE, Fraser R, Cartwright JE. Extravillous trophoblast and decidual 31. Macey MG, McCarthy DA, Vordermeier S, Newland AC, Brown KA. Effects of natural killer cells: a remodelling partnership. Hum Reprod Update (2012) cell purification methods on CD11b and L-selectin expression as well as adher- 18(4):458–71. doi:10.1093/humupd/dms015 ence and activation of leukocytes. J Immunol Methods (1995) 181(2):211–9. 11. Svensson-Arvelund J, Ernerudh J, Buse E, Cline JM, Haeger JD, Dixon doi:10.1016/0022- 1759(95)00003- S D, et al. The placenta in toxicology. Part II: systemic and local immune 32. Sacks GP, Studena K, Sargent IL, Redman CWG. Normal pregnancy and adaptations in pregnancy. Toxicol Pathol (2014) 42(2):327–38. doi:10.1177/ preeclampsia both produce inflammatory changes in peripheral blood leuko- 0192623313482205 cytes akin to those of sepsis. Am J Obstet Gynecol (1998) 179:80–6. doi:10.1016/ 12. Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev S0002- 9378(98)70254- 6 Immunol (2005) 5(12):953–64. doi:10.1038/nri1733 33. Naccasha N, Gervasi MT, Chaiworapongsa T, Berman S, Yoon BH, Maymon 13. Ziegler-Heitbrock L, Ancuta P, Crowe S, Dalod M, Grau V, Hart DN, et al. E, et al. Phenotypic and metabolic characteristics of monocytes and granulo- Nomenclature of monocytes and dendritic cells in blood. Blood (2010) cytes in normal pregnancy and maternal infection. Am J Obstet Gynecol (2001) 116(16):e74–80. doi:10.1182/blood- 2010- 02- 258558 185(5):1118–23. doi:10.1067/mob.2001.117682 14. Sunderkötter C, Nikolic T, Dillon MJ, Van Rooijen N, Stehling M, Drevets 34. Luppi P, Haluszczak C, Betters D, Richard CAH, Trucco M, DeLoia JA. Mono- DA, et al. Subpopulations of mouse blood monocytes differ in matura- cytes are progressively activated in the circulation of pregnant women. J Leukoc tion stage and inflammatory response. J Immunol (2004) 172(7):4410–7. Biol (2002) 72(5):874–84. doi:10.4049/jimmunol.172.7.4410 35. Luppi P, Haluszczak C, Trucco M, DeLoia JA. Normal pregnancy is asso- 15. Auffray C, Fogg D, Garfa M, Elain G, Join-Lambert O, Kayal S, et al. Monitor- ciated with peripheral leukocyte activation. Am J Reprod Immunol (2002) ing of blood vessels and tissues by a population of monocytes with patrolling 47(2):72–81. doi:10.1034/j.1600- 0897.2002.1o041.x behavior. Science (2007) 317(5838):666–70. doi:10.1126/science.1142883 36. Faas MM, Kunnen A, Dekker DC, Harmsen HJ, Aarnoudse JG, Abbas F, et al. 16. Fingerle G, Pforte A, Passlick B, Blumenstein M, Strobel M, Ziegler-Heitbrock Porphyromonas gingivalis and E-coli induce different cytokine production pat- HW. The novel subset of CD14+/CD16+ blood monocytes is expanded in terns in pregnant women. PLoS One (2014) 9(1):e86355. doi:10.1371/journal. sepsis patients. Blood (1993) 82(10):3170–6. pone.0086355 17. Zimmermann HW, Seidler S, Nattermann J, Gassler N, Hellerbrand C, Zer- 37. Beckmann I, Efraim SB, Vervoort M, Visser W, Wallenburg HC. Tumor necro- necke A, et al. Functional contribution of elevated circulating and hepatic non- sis factor-alpha in whole blood cultures of preeclamptic patients and healthy classical CD14CD16 monocytes to inflammation and human liver fibrosis. pregnant and nonpregnant women. Hypertens Pregnancy (2004) 23(3):319–29. PLoS One (2010) 5(6):e11049. doi:10.1371/journal.pone.0011049 doi:10.1081/PRG- 200030334 18. Mantovani A, Biswas SK, Galdiero MR, Sica A, Locati M. Macrophage plas- 38. Sacks GP, Redman CWG, Sargent IL. Monocytes are primed to produce the ticity and polarization in tissue repair and remodelling. J Pathol (2013) Th1 type cytokine IL-12 in normal human pregnancy: an intracellular flow 229(2):176–85. doi:10.1002/path.4133 cytometric analysis of peripheral blood mononuclear cells. Clin Exp Immunol 19. Porcheray F, Viaud S, Rimaniol AC, Léone C, Samah B, Dereuddre-Bosquet N, (2003) 131(3):490–7. doi:10.1046/j.1365- 2249.2003.02082.x et al. Macrophage activation switching: an asset for the resolution of inflam- 39. Faas MM, Moes H, Fijen JW, Muller Kobold AC, Tulleken JE, Zijlstra JG. mation. Clin Exp Immunol (2005) 142(3):481–9. doi:10.1111/j.365- 2249.2005. Monocyte intracellular cytokine production during human endotoxemia with 02934.x or without a second in vitro LPS challenge: effect of RWJ067657, a p36 20. Yang J, Zhang L, Yu C, Yang XF, Wang H. Monocyte and macrophage differ- MAP-kinase inhibitor, on LPS-hyporesponsiveness. Clin Exp Immunol (2002) entiation: circulation inflammatory monocyte as biomarker for inflammatory 127:337–43. doi:10.1046/j.1365- 2249.2002.01765.x diseases. Biomark Res (2014) 2(1):1. doi:10.1186/2050- 7771- 2- 1 40. Chen J, Ivashkiv LB. IFN-g abrogates endotoxin tolerance by facilitating toll- 21. Spahn JH, Kreisel D. Monocytes in sterile inflammation: recruitment and func- like receptor-induced chromatin remodeling. Proc Natl Acad Sci U S A (2010) tional consequences. Arch Immunol Ther Exp (Warsz) (2013) 62(3):187–94. 107(45):19438–43. doi:10.1073/pnas.1007816107 doi:10.1007/s00005- 013- 0267- 5 41. Melgert BN, Spaans F, Borghuis T, Klok PA, Groen B, Bolt A, et al. Pregnancy 22. Wegmann TG, Lin H, Guilbert L, Mosmann TR. Bidirectional cytokine and preeclampsia affect monocyte subsets in humans and rats. PLoS One (2012) interactions in the maternal-fetal relationship: is successful pregnancy a Th2 7(9):e45229. doi:10.1371/journal.pone.0045229 phenomenon? Immunol Today (1993) 14:353–6. doi:10.1016/0167- 5699(93) 42. Rossol M, Kraus S, Pierer M, Baerwald C, Wagner U. The CD14(bright) 90235- D CD16+ monocyte subset is expanded in rheumatoid arthritis and promotes Frontiers in Immunology | Inflammation June 2014 | Volume 5 | Article 298 | 8 Faas et al. Monocytes and macrophages in pregnancy and pre-eclampsia expansion of the Th17 cell population. Arthritis Rheum (2012) 64(3):671–7. 61. Steinberg G, Khankin EV, Karumanchi SA. Angiogenic factors and preeclamp- doi:10.1002/art.33418 sia. Thromb Res (2009) 123(Suppl 2):S93–9. doi:10.1016/S0049- 3848(09) 43. Moniuszko M, Bodzenta-Lukaszyk A, Kowal K, Lenczewska D, Dabrowska M. 70020- 9 Enhanced frequencies of CD14++CD16+, but not CD14+CD16+, periph- 62. Redman CW, Sargent IL. Placental debris, oxidative stress and pre-eclampsia. eral blood monocytes in severe asthmatic patients. Clin Immunol (2009) Placenta (2000) 21(7):597–602. doi:10.1053/plac.2000.0560 130(3):338–46. doi:10.1016/j.clim.2008.09.011 63. Pang ZJ, Xing FQ. Comparative study on the expression of cytokine – receptor 44. Al-ofi E, Coffelt SB, Anumba DO. Monocyte subpopulations from pre- genes in normal and preeclamptic human placentas using DNA microarrays. eclamptic patients are abnormally skewed and exhibit exaggerated responses to J Perinat Med (2003) 31(2):153–62. doi:10.1515/JPM.2003.021 toll-like receptor ligands. PLoS One (2012) 7(7):e42217. doi:10.1371/journal. 64. Benyo DF, Smarason A, Redman CW, Sims C, Conrad KP. Expression of pone.0042217 inflammatory cytokines in placentas from women with preeclampsia. J Clin 45. Kelly RW. Inflammatory mediators and parturition. Rev Reprod (1996) Endocrinol Metab (2001) 86(6):2505–12. doi:10.1210/jc.86.6.2505 1(2):89–96. 65. Wang Y, Walsh SW. TNF alpha concentrations and mRNA expression are 46. Bokström H, Brännström M, Alexandersson M, Norström A. Leukocyte sub- increased in preeclamptic placentas. J Reprod Immunol (1996) 32(2):157–69. populations in the human uterine cervical stroma at early and term pregnancy. doi:10.1016/S0165- 0378(96)00998- 9 Hum Reprod (1997) 12(3):586–90. doi:10.1093/humrep/12.3.586 66. Hennessy A, Pilmore HL, Simmons LA, Painter DM. A deficiency of placental 47. Luppi P, Irwin TE, Simhan H, Deloia JA. CD11b Expression on circulating IL-10 in preeclampsia. J Immunol (1999) 163(6):3491–5. leukocytes increases in preparation for parturition. Am J Reprod Immunol 67. Rein DT, Breidenbach M, Hönscheid B, Friebe-Hoffmann U, Engel H, Göhring (2004) 52(5):323–9. doi:10.1111/j.1600- 0897.2004.00229.x UJ, et al. Preeclamptic women are deficient of interleukin-10 as assessed by 48. Vega-Sanchez R, Gomez-Lopez N, Flores-Pliego A, Clemente-Galvan S, cytokine release of trophoblast cells in vitro. Cytokine (2003) 23(4–5):119–25. Estrada-Gutierrez G, Zentella-Dehesa A, et al. Placental blood leukocytes are doi:10.1016/S1043- 4666(03)00220- 5 functional and phenotypically different than peripheral leukocytes during 68. Vince GS, Starkey PM, Austgulen R, Kwaitkowski D, Redman CWG. human labor. J Reprod Immunol (2010) 84(1):100–10. doi:10.1016/j.jri.2009. Interleukin-6, tumour necrosis factor and soluble tumour necrosis factor recep- 08.002 tors in women with pre-eclampsia. Br J Obstet Gynaecol (1995) 102:20–5. 49. Gervasi MT, Chaiworapongsa T, Naccasha N, Blackwell S, Yoon BH, Maymon doi:10.1111/j.1471- 0528.1995.tb09020.x E, et al. Phenotypic and metabolic characteristics of maternal monocytes and 69. Conrad KP, Miles TM, Benyo DF. Circulating levels of immunoreactive granulocytes in preterm labor with intact membranes. Am J Obstet Gynecol cytokines in women with preeclampsia. Am J Reprod Immunol (1998) (2001) 185(5):1124–9. doi:10.1067/mob.2001.117311 40(2):102–11. doi:10.1111/j.1600- 0897.1998.tb00398.x 50. Borzychowski AM, Sargent IL, Redman CW. Inflammation and pre-eclampsia. 70. Faas MM, Schuiling GA, Baller JFW, Visscher CA, Bakker WW. A new animal Semin Fetal Neonatal Med (2006) 11(5):309–16. doi:10.1016/j.siny.2006.04.001 model for human pre-eclampsia: ultralow dose endotoxin infusion in preg- 51. Gervasi MT, Chaiworapongsa T, Pacora P, Naccasha N, Yoon BH, May- nant rats. Am J Obstet Gynecol (1994) 171:158–64. doi:10.1016/0002- 9378(94) mon E, et al. Phenotypic and metabolic characteristics of monocytes and 90463- 4 granulocytes in preeclampsia. Am J Obstet Gynecol (2001) 185(4):792–7. 71. Kunnen A, Van Pampus MG, Aarnoudse JG, van der Schans CP, Abbas F, Faas doi:10.1067/mob.2001.117311 MM. The effect of Porphyromonas gingivalis lipopolysaccharide on pregnancy 52. Luppi P, Tse H, Lain KY, Markovic N, Piganelli JD, DeLoia JA. Preeclampsia acti- in the rat. Oral Dis (2013). doi:10.1111/odi.12177 vates circulating immune cells with engagement of the NF-kappaB pathway. Am 72. Kunnen A, Dekker DC, van Pampus MG, Harmsen HJ, Aarnoudse JG, Abbas J Reprod Immunol (2006) 56(2):135–44. doi:10.1111/j.1600- 0897.2006.00386. F, et al. Cytokine production induced by non-encapsulated and encapsu- x lated Porphyromonas gingivalis strains. Arch Oral Biol (2012) 57(11):1558–66. 53. Sakai M, Tsuda H, Tanebe K, Sasaki Y, Saito S. Interleukin-12 secretion by doi:10.1016/j.archoralbio.2012.07.013 peripheral blood mononuclear cells is decreased in normal pregnant sub- 73. Conde-Agudelo A, Villar J, Lindheimer M. Maternal infection and risk of jects and increased in preeclamptic patients. Am J Reprod Immunol (2002) preeclampsia: systematic review and metaanalysis. Am J Obstet Gynecol (2008) 47(2):91–7. doi:10.1034/j.1600- 0897.2002.1o020.x 198(1):7–22. doi:10.1016/j.ajog.2007.07.040 54. Peraçoli JC, Rudge MV, Peraçoli MT. Tumor necrosis factor-alpha in gestation 74. Soares MJ, Chakraborty D, Karim Rumi MA, Konno T, Renaud SJ. Rat placen- and puerperium of women with gestational hypertension and pre-eclampsia. tation: an experimental model for investigating the hemochorial maternal-fetal Am J Reprod Immunol (2007) 57(3):177–85. doi:10.1111/j.1600- 0897.2006. interface. Placenta (2012) 33(4):233–43. doi:10.1016/j.placenta.2011.11.026 00455.x 75. Faas MM, Schuiling GA, Linton EA, Sargent IL, Redman CW. Activation of 55. Veenstra van Nieuwenhoven AL, Moes H, Heineman MJ, Santema J, Faas MM. peripheral leukocytes in rat pregnancy and experimental preeclampsia. Am Cytokine production by monocytes, NK cells and lymphocytes is different in J Obstet Gynecol (2000) 182(2):351–7. doi:10.1016/S0002- 9378(00)70223- 7 preeclamptic patients as compared with normal pregnant women. Hypertens 76. Faas MM, Broekema M, Moes H, van der Schaaf G, Heineman MJ, de Vos P. Pregnancy (2008) 27(3):207–24. doi:10.1080/10641950701885006 Altered monocyte function in experimental preeclampsia in the rat. Am J Obstet 56. Brewster JA, Orsi NM, Gopichandran N, Ekbote UV, Cadogan E, Walker Gynecol (2004) 191(4):1192–8. doi:10.1016/j.ajog.2004.03.041 JJ. Host inflammatory response profiling in preeclampsia using an in vitro 77. Faas MM, van der Schaaf G, Borghuis T, Jongman RM, van Pampus MG, de whole blood stimulation model. Hypertens Pregnancy (2008) 27(1):1–16. Vos P, et al. Extracellular ATP induces albuminuria in pregnant rats. Nephrol doi:10.1080/10641950701826067 Dial Transplant (2010) 25(8):2468–78. doi:10.1093/ndt/gfq095 57. Sacks GP, Clover LM, Bainbridge DR, Redman CW, Sargent IL. Flow cyto- 78. LaMarca B, Speed J, Fournier L, Babcock SA, Berry H, Cockrell K, et al. metric measurement of intracellular Th1 and Th2 cytokine production by Hypertension in response to chronic reductions in uterine perfusion in preg- human villous and extravillous cytotrophoblast. Placenta (2001) 22(6):550–9. nant rats: effect of tumor necrosis factor-alpha blockade. Hypertension (2008) doi:10.1053/plac.2001.0686 52(6):1161–7. doi:10.1161/HYPERTENSIONAHA.108.120881 58. Redman CW, Tannetta DS, Dragovic RA, Gardiner C, Southcombe JH, Collett 79. Spaans F, Melgert BN, Borghuis T, Klok PA, de Vos P, Bakker WW, et al. Extra- GP, et al. Review: does size matter? Placental debris and the pathophysiology cellular adenosine triphosphate affects systemic and kidney immune cell pop- of pre-eclampsia. Placenta (2012) 33(Suppl):S48–54. doi:10.1016/j.placenta. ulations in pregnant rats. Am J Reprod Immunol (2014). doi:10.1111/aji.12267 2011.12.006 80. Faas MM, Schuiling GA, Baller JFW, Bakker WW. Glomerular inflammation 59. Bianchi DW, Zickwolf GK, Weil GJ, Sylvester S, DeMaria MA. Male fetal prog- in pregnant rats after infusion of low dose endotoxin: an immunohistological enitor cells persist in maternal blood for as long as 27 years postpartum. Proc study in experimental pre-eclampsia. Am J Pathol (1995) 147:1510–8. Natl Acad Sci U S A (1996) 93(2):705–8. doi:10.1073/pnas.93.2.705 81. Bulmer JN, Morrison L, Longfellow M, Ritson A, Pace D. Granulated lym- 60. Faas MM, van Pampus MG, Anninga ZA, Salomons J, Westra IM, Donker RB, phocytes in human endometrium: histochemical and immunohistochemical et al. Plasma from preeclamptic women activates endothelial cells via mono- studies. Hum Reprod (1991) 6(6):791–8. cyte activation in vitro. J Reprod Immunol (2010) 87(1–2):28–38. doi:10.1016/ 82. Klentzeris LD, Bulmer JN, Warren A, Morrison L, Li TC, Cooke ID. Endome- j.jri.2010.07.005 trial lymphoid tissue in the timed endometrial biopsy: morphometric and www.frontiersin.org June 2014 | Volume 5 | Article 298 | 9 Faas et al. Monocytes and macrophages in pregnancy and pre-eclampsia immunohistochemical aspects. Am J Obstet Gynecol (1992) 167(3):667–74. 104. Thaxton JE, Sharma S. Interleukin-10: a multi-faceted agent of pregnancy. doi:10.1016/S0002- 9378(11)91568- 3 Am J Reprod Immunol (2010) 63(6):482–91. doi:10.1111/j.1600- 0897.2010. 83. Hunt JS, Miller L, Platt JS. Hormonal regulation of uterine macrophages. Dev 00810.x Immunol (1998) 6(1–2):105–10. 105. Roth I, Corry DB, Locksley RM, Abrams JS, Litton MJ, Fisher SJ. Human pla- 84. Jones RL, Hannan NJ, Kaitu’u TJ, Zhang J, Salamonsen LA. Identification of cental cytotrophoblasts produce the immunosuppressive cytokine interleukin chemokines important for leukocyte recruitment to the human endometrium 10. J Exp Med (1996) 184(2):539–48. doi:10.1084/jem.184.2.539 at the times of embryo implantation and menstruation. J Clin Endocrinol Metab 106. Kim SY, Romero R, Tarca AL, Bhatti G, Kim CJ, Lee J, et al. Methylome (2004) 89(12):6155–67. doi:10.1210/jc.2004- 0507 of fetal and maternal monocytes and macrophages at the feto-maternal inter- 85. Bulmer JN, Williams PJ, Lash GE. Immune cells in the placental bed. Int J Dev face. Am J Reprod Immunol (2012) 68(1):8–27. doi:10.1111/j.1600- 0897.2012. Biol (2010) 54(2–3):281–94. doi:10.1387/ijdb.082763jb 01108.x 86. Bulmer JN, Morrison L, Smith JC. Expression of class II MHC gene prod- 107. Houser BL, Tilburgs T, Hill J, Nicotra ML, Strominger JL. Two unique ucts by macrophages in human uteroplacental tissue. Immunology (1988) human decidual macrophage populations. J Immunol (2011) 186(4):2633–42. 63(4):707–14. doi:10.4049/jimmunol.1003153 87. Lessin DL, Hunt JS, King CR, Wood GW. Antigen expression by cells near the 108. Petroff MG, Sedlmayr P, Azzola D, Hunt JS. Decidual macrophages are poten- maternal-fetal interface. Am J Reprod Immunol Microbiol (1988) 16(1):1–7. tially susceptible to inhibition by class Ia and class Ib HLA molecules. J Reprod 88. Williams PJ, Searle RF, Robson SC, Innes BA, Bulmer JN. Decidual leuko- Immunol (2002) 56(1–2):3–17. doi:10.1016/S0165- 0378(02)00024- 4 cyte populations in early to late gestation normal human pregnancy. J Reprod 109. Abumaree MH, Chamley LW, Badri M, El-Muzaini MF. Trophoblast debris Immunol (2009) 82(1):24–31. doi:10.1016/j.jri.2009.08.001 modulates the expression of immune proteins in macrophages: a key to mater- 89. Bulmer JN, Johnson PM. Macrophage populations in the human placenta and nal tolerance of the fetal allograft? J Reprod Immunol (2012) 94(2):131–41. amniochorion. Clin Exp Immunol (1984) 57(2):393–403. doi:10.1016/j.jri.2012.03.488 90. Tafuri A, Alferink J, Moller P, Hammerling GJ, Arnold B. T cell awareness 110. Fadok VA, Chimini G. The phagocytosis of apoptotic cells. Semin Immunol of paternal alloantigens during pregnancy. Science (1995) 270(5236):630–3. (2001) 13(6):365–72. doi:10.1006/smim.2001.0333 doi:10.1126/science.270.5236.630 111. Van Ginderachter JA, Movahedi K, Hassanzadeh Ghassabeh G, Meerschaut S, 91. Renaud SJ, Graham CH. The role of macrophages in utero-placental inter- Beschin A, Raes G, et al. Classical and alternative activation of mononuclear actions during normal and pathological pregnancy. Immunol Invest (2008) phagocytes: picking the best of both worlds for tumor promotion. Immunobi- 37(5):535–64. doi:10.1080/08820130802191375 ology (2006) 211(6–8):487–501. doi:10.1016/j.imbio.2006.06.002 92. Singh U, Nicholson G, Urban BC, Sargent IL, Kishore U, Bernal AL. Immuno- 112. Schonkeren D, van der Hoorn ML, Khedoe P, Swings G, van Beelen E, Claas logical properties of human decidual macrophages – a possible role in F, et al. Differential distribution and phenotype of decidual macrophages in intrauterine immunity. Reproduction (2005) 129(5):631–7. doi:10.1530/rep.1. preeclamptic versus control pregnancies. Am J Pathol (2011) 178(2):709–17. 00331 doi:10.1016/j.ajpath.2010.10.011 93. Smith SD, Dunk CE, Aplin JD, Harris LK, Jones RL. Evidence for immune cell 113. Schonkeren D, Swings G, Roberts D, Claas F, de Heer E, Scherjon S. Pregnancy involvement in decidual spiral arteriole remodeling in early human pregnancy. close to the edge: an immunosuppressive infiltrate in the chorionic plate of pla- Am J Pathol (2009) 174(5):1959–71. doi:10.2353/ajpath.2009.080995 centas from uncomplicated egg cell donation. PLoS One (2012) 7(3):e32347. 94. Engert S, Rieger L, Kapp M, Becker JC, Dietl J, Kämmerer U. Profiling doi:10.1371/journal.pone.0032347 chemokines, cytokines and growth factors in human early pregnancy decidua 114. Williams PJ, Bulmer JN, Searle RF, Innes BA, Robson SC. Altered decidual by protein array. Am J Reprod Immunol (2007) 58(2):129–37. doi:10.1111/j. leukocyte populations in the placental bed in pre-eclampsia and foetal growth 1600- 0897.2007.00498.x restriction: a comparison with late normal pregnancy. Reproduction (2009) 95. Gustafsson C, Mjösberg J, Matussek A, Geffers R, Matthiesen L, Berg G, 138(1):177–84. doi:10.1530/REP- 09- 0007 et al. Gene expression profiling of human decidual macrophages: evidence 115. Bürk MR, Troeger C, Brinkhaus R, Holzgreve W, Hahn S. Severely reduced for immunosuppressive phenotype. PLoS One (2008) 3(4):e2078. doi:10.1371/ presence of tissue macrophages in the basal plate of pre-eclamptic placentae. journal.pone.0002078 Placenta (2001) 22(4):309–16. doi:10.1053/plac.2001.0624 96. Hazan AD, Smith SD, Jones RL, Whittle W, Lye SJ, Dunk CE. Vascular-leukocyte 116. Reister F, Frank HG, Kingdom JC, Heyl W, Kaufmann P, Rath W, et al. interactions: mechanisms of human decidual spiral artery remodeling in vitro. Macrophage-induced apoptosis limits endovascular trophoblast invasion in Am J Pathol (2010) 177(2):1017–30. doi:10.2353/ajpath.2010.091105 the uterine wall of preeclamptic women. Lab Invest (2001) 81(8):1143–52. 97. Abrahams VM, Kim YM, Straszewski SL, Romero R, Mor G. Macrophages doi:10.1038/labinvest.3780326 and apoptotic cell clearance during pregnancy. Am J Reprod Immunol (2004) 117. Wilczynski JR, Tchórzewski H, Banasik M, Głowacka E, Wieczorek A, Lewkow- 51(4):275–82. doi:10.1111/j.1600- 0897.2004.00156.x icz P, et al. Lymphocyte subset distribution and cytokine secretion in third 98. Piacentini M, Autuori F. Immunohistochemical localization of tissue transglut- trimester decidua in normal pregnancy and preeclampsia. Eur J Obstet Gynecol aminase and Bcl-2 in rat uterine tissues during embryo implantation and post- Reprod Biol (2003) 109(1):8–15. doi:10.1016/S0301- 2115(02)00350- 0 partum involution. Differentiation (1994) 57(1):51–61. doi:10.1046/j.1432- 118. Kim JS, Romero R, Cushenberry E, Kim YM, Erez O, Nien JK, et al. Distribu- 0436.1994.5710051.x tion of CD14+ and CD68+ macrophages in the placental bed and basal plate of 99. Cupurdija K, Azzola D, Hainz U, Gratchev A, Heitger A, Takikawa O, women with preeclampsia and preterm labor. Placenta (2007) 28(5–6):571–6. et al. Macrophages of human first trimester decidua express markers asso- doi:10.1016/j.placenta.2006.07.007 ciated to alternative activation. Am J Reprod Immunol (2004) 51(2):117–22. 119. Hayashi M, Hoshimoto K, Ohkura T, Inaba N. Increased levels of doi:10.1046/j.8755- 8920.2003.00128.x macrophage colony-stimulating factor in the placenta and blood in preeclamp- 100. Kämmerer U, Eggert AO, Kapp M, McLellan AD, Geijtenbeek TB, Dietl J, et al. sia. Am J Reprod Immunol (2002) 47(1):19–24. doi:10.1034/j.1600- 0897.2002. Unique appearance of proliferating antigen-presenting cells expressing DC- 1o035.x SIGN (CD209) in the decidua of early human pregnancy. Am J Pathol (2003) 120. Katabuchi H, Yih S, Ohba T, Matsui K, Takahashi K, Takeya M, et al. Character- 162(3):887–96. doi:10.1016/S00002- 9440(10)63884- 9 ization of macrophages in the decidual atherotic spiral artery with special ref- 101. Laskarin G, Cupurdija K, Tokmadzic VS, Dorcic D, Dupor J, Juretic K, et al. The erence to the cytology of foam cells. Med Electron Microsc (2003) 36(4):253–62. presence of functional mannose receptor on macrophages at the maternal-fetal doi:10.1007/s00795- 003- 0223- 2 interface. Hum Reprod (2005) 20(4):1057–66. doi:10.1093/humrep/deh740 121. Reister F, Frank HG, Heyl W, Kosanke G, Huppertz B, Schröder W, et al. 102. Svensson J, Jenmalm MC, Matussek A, Geffers R, Berg G, Ernerudh J. The distribution of macrophages in spiral arteries of the placental bed in Macrophages at the fetal-maternal interface express markers of alterna- pre-eclampsia differs from that in healthy patients. Placenta (1999) 20(2– tive activation and are induced by M-CSF and IL-10. J Immunol (2011) 3):229–33. doi:10.1053/plac.1998.0373 187(7):3671–82. doi:10.4049/jimmunol.1100130 122. Haeger M, Unander M, Norder-Hansson B, Tylman M, Bengtsson A. Comple- 103. Daiter E, Pampfer S, Yeung YG, Barad D, Stanley ER, Pollard JW. Expression of ment, neutrophil, and macrophage activation in women with severe preeclamp- colony-stimulating factor-1 in the human uterus and placenta. J Clin Endocrinol sia and the syndrome of hemolysis, elevated liver enzymes, and low platelet Metab (1992) 74(4):850–8. doi:10.1210/jc.74.4.850 count. Obstet Gynecol (1992) 79(1):19–26. Frontiers in Immunology | Inflammation June 2014 | Volume 5 | Article 298 | 10 Faas et al. Monocytes and macrophages in pregnancy and pre-eclampsia 123. Staff AC, Johnsen GM, Dechend R, Redman CW. Preeclampsia and uteropla- 129. Spaans F, Melgert BN, Chiang C, Borghuis T, Klok PA, De Vos P, et al. Extra- cental acute atherosis: immune and inflammatory factors. J Reprod Immunol cellular ATP decreases trophoblast invasion, spiral artery remodeling and (2014) 101-102:120–6. doi:10.1016/j.jri.2013.09.001 immune cells in the mesometrial triangle in pregnant rats. Placenta (2014). 124. Staff AC, Dechend R, Redman CW. Review: preeclampsia, acute atherosis of the doi:10.1016/j.placenta.2014.05.013 spiral arteries and future cardiovascular disease: two new hypotheses. Placenta (2013) 34(Suppl):S73–8. doi:10.1016/j.placenta.2012.11.022 Conflict of Interest Statement: The authors declare that the research was conducted 125. Prins JR, Faas MM, Melgert BN, Huitema S, Timmer A, Hylkema MN, in the absence of any commercial or financial relationships that could be construed et al. Altered expression of immune-associated genes in first-trimester as a potential conflict of interest. human decidua of pregnancies later complicated with hypertension or foetal growth restriction. Placenta (2012) 33(5):453–5. doi:10.1016/j.placenta.2012. Received: 01 May 2014; paper pending published: 26 May 2014; accepted: 12 June 2014; 02.010 published online: 30 June 2014. 126. Helige C, Ahammer H, Hammer A, Huppertz B, Frank HG, Dohr G. Tro- Citation: Faas MM, Spaans F and De Vos P (2014) Monocytes and macrophages in phoblastic invasion in vitro and in vivo: similarities and differences. Hum pregnancy and pre-eclampsia. Front. Immunol. 5:298. doi: 10.3389/fimmu.2014.00298 Reprod (2008) 23(10):2282–91. doi:10.1093/humrep/den198 This article was submitted to Inflammation, a section of the journal Frontiers in 127. Renaud SJ, Postovit LM, Macdonald-Goodfellow SK, McDonald GT, Caldwell Immunology. JD, Graham CH. Activated macrophages inhibit human cytotrophoblast inva- Copyright © 2014 Faas , Spaans and De Vos. This is an open-access article distributed siveness in vitro. Biol Reprod (2005) 73(2):237–43. doi:10.1095/biolreprod.104. under the terms of the Creative Commons Attribution License (CC BY). The use, dis- 038000 tribution or reproduction in other forums is permitted, provided the original author(s) 128. Renaud SJ, Macdonald-Goodfellow SK, Graham CH. Coordinated regulation or licensor are credited and that the original publication in this journal is cited, in of human trophoblast invasiveness by macrophages and interleukin 10. Biol accordance with accepted academic practice. No use, distribution or reproduction is Reprod (2007) 76(3):448–54. doi:10.1095/biolreprod.106.055376 permitted which does not comply with these terms. www.frontiersin.org June 2014 | Volume 5 | Article 298 | 11 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Frontiers in Immunology Pubmed Central

Monocytes and Macrophages in Pregnancy and Pre-Eclampsia

Frontiers in Immunology , Volume 5 – Jun 30, 2014

Loading next page...
 
/lp/pubmed-central/monocytes-and-macrophages-in-pregnancy-and-pre-eclampsia-FsIjg30ZuH

References (284)

Publisher
Pubmed Central
Copyright
Copyright © 2014 Faas, Spaans and De Vos.
ISSN
1664-3224
eISSN
1664-3224
DOI
10.3389/fimmu.2014.00298
Publisher site
See Article on Publisher Site

Abstract

REVIEW ARTICLE published: 30 June 2014 doi: 10.3389/fimmu.2014.00298 Monocytes and macrophages in pregnancy and pre-eclampsia Marijke M. Faas*, Floor Spaans and Paul De Vos Immunoendocrinology, Department of Pathology and Medical Biology, Division of Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands Edited by: Preeclampsia is an important complication in pregnancy, characterized by hypertension Sinuhe Hahn, University Hospital and proteinuria in the second half of pregnancy. Generalized activation of the inflamma- Basel, Switzerland tory response is thought to play a role in the pathogenesis of pre-eclampsia. Monocytes Reviewed by: may play a central role in this inflammatory response. Monocytes are short lived cells Juan Carlos Salazar, Connecticut Children’s Medical Center, USA that mature in the circulation and invade into tissues upon an inflammatory stimulus and Fulvio D’Acquisto, Queen Mary develop into macrophages. Macrophages are abundantly present in the endometrium and University of London, UK play a role in implantation and placentation in normal pregnancy. In pre-eclampsia, these *Correspondence: macrophages appear to be present in larger numbers and are also activated. In the present Marijke M. Faas, review, we focused on the role of monocytes and macrophages in the pathophysiology of Immunoendocrinology, Department pre-eclampsia. of Pathology and Medical Biology, Division of Medical Biology, Keywords: pregnancy, pre-eclampsia, monocytes, macrophages, decidua, placenta University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen 7913 GZ, Netherlands e-mail: m.m.faas@umcg.nl INTRODUCTION conditions, may lead to a better understating of the inflammatory Preeclampsia is one of the leading complications of pregnancy, response in normal pregnancy and in pre-eclampsia. Therefore, characterized by hypertension and proteinuria and developing in the present paper will review the systemic and local changes in the second half of pregnancy (1, 2). Preeclampsia is suggested to the decidua in monocytes and macrophages and their subsets dur- be a two stage disease: the first stage being poor placentation (3). ing healthy human pregnancy and pre-eclampsia. Examples from The second stage is the production of pro-inflammatory factors by animal models will also be included. the diseased placenta, which activates the systemic inflammatory response, leading to the signs of pre-eclampsia (3). MONOCYTES AND MACROPHAGES AND THEIR SUBSETS MONOCYTES During normal pregnancy, the circulation of peripheral blood through the placenta results in direct or indirect contact of mater- Monocytes arise from precursors in the bone marrow and com- prise about 5–10% of the circulating blood leukocytes. They cir- nal immune cells with the placenta. This may activate circulating immune cells, especially monocytes (4, 5). In pre-eclampsia, due to culate in the blood for a few days before migrating into tissues to become macrophages or dendritic cells (12). They have important production of pro-inflammatory factors from the placenta (6–9), monocytes are even further activated and together with activation functions in homeostasis, tissue repair, and inflammation (12). It has recently become clear that circulating monocytes are a hetero- of other inflammatory cells, such as granulocytes and endothelial cells, finally induce the full blown syndrome of pre-eclampsia (3). geneous population (12). In humans, the monocyte subsets can be At the maternal–fetal interface, from the beginning of a healthy distinguished based on the expression of CD14, the lipopolysac- charide (LPS) receptor. The main subset (comprising about 90– pregnancy, there is an increase of innate immune cells, such as macrophages and NK cells (10). These macrophages and NK cells 95% of the monocytes) is a subset expressing high levels of CD14, but lacking CD16 (FcgR-III) expression. Since this is the main sub- may have a local immune function, however, they also appear to be important for placental development by promoting trophoblast sets and until recently thought to be the only subset, this subset is usually called “classical subset”. The second subset of monocytes recruitment, spiral artery remodeling, and angiogenesis (11). The present review will focus on macrophages at the maternal–fetal is characterized by low expression of CD14 together with CD16. This subset is often called the non-classical subset. More recently, interface. In normal pregnancy, most of the macrophages at the maternal–fetal interface are M2 macrophages, i.e., immunomod- a third, intermediate subset of monocytes has been defined, called the intermediate subset (13). This subset is characterized by high ulatory macrophages (11). In pre-eclampsia, there appear to be increased numbers of M1 macrophages, suggesting a role for these expression of CD14 in combination with expression of CD16 and macrophages in the poor placental development in pre-eclampsia. is a separate subset of monocytes. It has been suggested that classi- Monocytes and macrophages may thus play an important cal monocytes arise from the bone marrow and mature into non- role in healthy pregnancy as well in the pathophysiology of pre- classical monocytes via intermediate monocytes (13, 14). These subsets differ in many respects, including expression of adhesion eclampsia. Further insight into the role of these cells in these www.frontiersin.org June 2014 | Volume 5 | Article 298 | 1 Faas et al. Monocytes and macrophages in pregnancy and pre-eclampsia molecules and chemokine receptors and function [reviewed in Ref. changes in regulatory T cells (26, 27) and Th17 cells (27). It has (12, 13)]. Classical monocytes are professional phagocytes that been suggested, that to compensate for such changes in the specific can generate reactive oxygen species (ROS) and produce cytokines immune response, also the innate immune response has to adapt to in response to toll-like receptor dependent activation by f.i. LPS. pregnancy. This has most often been shown by increased numbers Non-classical monocytes are weak phagocytes and do not gener- of circulating monocytes and granulocytes, resulting in increased ate ROS, but are more efficient producers of pro-inflammatory number of total leukocytes during pregnancy (28–30). Here, we cytokines after TLR dependent activation (12). This subset has will discuss changes in monocytes during healthy pregnancy and been shown to have a longer half-life and localize to both rest- in pre-eclampsia. ing and inflamed tissue (12). They crawl on the luminal side Although it has been known for a long time that leukocyte of the endothelium and survey endothelial cells and tissues for numbers increase during pregnancy, at that time this was not rec- damage and infection (13). Upon damage or infection, they may ognized as a sign of generalized inflammation in pregnant women. rapidly invade the tissue and initiate the inflammatory response With the introduction of new techniques, most importantly, flow (15). Non-classical monocytes have been shown to be increased in cytometry, function and activation status of leukocytes monocyte various inflammatory diseases (13, 16, 17). could be examined by measuring expression of markers of acti- vation and production of intracellular cytokines. Moreover, the MACROPHAGES flow cytometric analysis did not require isolation of cells from Macrophages are located in all body tissues, where they are impor- whole blood, as measurements could be done in whole blood. tant in detecting, ingesting, and processing foreign material, dead This represents the in vivo situation much better, since isolation cells, and other debris (12). Monocytes are macrophage precursors of leukocytes from blood may activate these cells (31). Using (12); monocytes can be recruited into tissues, to replenish steady the whole blood method, Sacks et al. (32) showed phenotypical state macrophages or can be recruited in inflammatory conditions activation of monocytes during pregnancy, by showing increased (12), where they mature into macrophages (or dendritic cells) expression of the activation markers CD11b, CD14, and CD64 on (12). Macrophages play an important role in the innate and adap- monocytes from pregnant women as compared with monocytes tive immune responses to pathogens and are important mediators from non-pregnant women. Afterward, these results have been of inflammatory processes (12). However, they also have anti- confirmed by others (33–35). inflammatory properties, as they are also involved in the resolution The monocytes are also functionally changed in pregnant of the inflammation (12). Indeed, several macrophage subsets with women. This has, for instance, been demonstrated by measuring distinct functions have been described. Broadly, they can be clas- the production of oxygen free radicals (32), which is increased in sified into two groups: M1 or classically activated macrophages, pregnant women. Although some authors have shown increased and M2 or alternatively activated macrophages (18). These sub- cytokine production by non-stimulated monocytes from pregnant sets differ in receptor, cytokine, and chemokine expression and women vs. non-pregnant women (34), others could not confirm in effector function (18). M1 macrophages are microbicidal and this finding and only observed cytokine production by stimulated inflammatory, M2 macrophages are immunomodulatory, which monocytes (8, 30). Whether stimulated cytokine production of can induce tolerance and the resolution of inflammation, and pregnant monocytes is increased or decreased as compared to are only weak microbicidal (18). It has been suggested that these non-pregnant women seems to depend on the stimulus. After two populations may be extreme ends of polarization and that stimulation with only LPS cytokine production by monocytes macrophages may actively switch their phenotype, depending on from pregnant women was decreased as compared with cytokine the environment (19). production by monocytes from non-pregnant women (30, 36, 37). There is debate on the fate of the different monocyte subsets; it However, after stimulation of monocytes with both LPS and IFNg, is unclear whether tissue macrophages are derived from a specific monocytes of pregnant women showed increased cytokine pro- monocyte subset or from either subset randomly (12). It has been duction as compared with monocytes from non-pregnant women suggested that classical monocytes preferentially differentiate into (38). Although these findings seem contradictory, they can be M1 macrophages, while the non-classical monocytes preferentially explained as follows: decreased cytokine production of mono- differentiate into M2 macrophages during inflammation (20). cytes from pregnant women following LPS stimulation is a sign However, various studies have shown that such a strict distinction of activation of monocytes, since activated monocytes become between differentiation of classical and non-classical monocytes tolerant to LPS (39). IFNg, however, abrogates LPS tolerance may not be very likely and that it may depend on the model and (40). Therefore, if LPS tolerance is abrogated by IFNg during the inflammatory stimulus whether a monocyte differentiates into pregnancy, monocytes produce increased amounts of cytokines an M1 or M2 macrophage (20, 21). during pregnancy. The above mentioned studies have been per- formed in the third trimester of pregnancy and based on all MONOCYTES IN PREGNANCY above mentioned data, it is now generally accepted that mono- During normal pregnancy, the female immune system has to adapt cytes are activated during pregnancy. However, little is known to the presence of the semi-allogeneic fetus. Many changes in the about monocyte activation during the course of pregnancy. How- peripheral circulation have been observed, both in the specific ever, gradually developing monocyte activation may occur during and innate immune response. In the specific immune response, a the course of pregnancy, since one paper showed progressive phe- decreased Th1/Th2 ratio has been observed in both T cells (22–24) notypical activation of monocytes from the first trimester to the as well as in NK cells (23, 25). These changes may be associated with third trimester (34). Frontiers in Immunology | Inflammation June 2014 | Volume 5 | Article 298 | 2 Faas et al. Monocytes and macrophages in pregnancy and pre-eclampsia MONOCYTE SUBSETS IN PREGNANCY Al-ofi et al. included a more heterogeneous group of pre-eclamptic In the studies presented above, monocytes have been characterized women). by CD14 expression, indicating that mainly classical monocytes have been studied in pregnancy. Recently, we conducted a study POSSIBLE MECHANISMS OF MONOCYTE ACTIVATION IN PREGNANCY in which we identified the three subtypes of monocytes in preg- AND PRE-ECLAMPSIA nant women (41). We showed a decreased number of classical The exact mechanisms involved in the activation of monocytes monocytes and an increased number of intermediate monocytes in during pregnancy and pre-eclampsia remain unknown. The most healthy pregnancy. These results are in line with the suggestion that obvious suggestion is that the placenta is involved. Peripheral pregnancy is an inflammatory condition, since in other inflamma- monocytes circulate through the placental circulation and come tory diseases, this intermediate subset has also been shown to be into close contact with the semi-allogeneic villous syncytiotro- increased (42, 43). Our data, however, were not in line with data phoblast (Figure 1). This may activate monocytes. This notion of Al-ofi et al. (44), who showed increased numbers of classical is supported by the fact that monocytes become activated dur- monocytes and decreased numbers of non-classical monocytes in ing their passage through the placenta (5). It is, however, unsure pregnant vs. non-pregnant women. The reason for this difference whether this activation of monocytes occurs due to direct contact, is unclear, but may be due to differences in experimental meth- since several soluble placental products, such as cytokines (57), ods. Further studies are warranted to evaluate whether the subsets placental microparticles (58), fetal DNA (59), released into the respond differently to stimulation in pregnant and non-pregnant maternal circulation, may also activate monocytes (60). women. Many factors may be involved in further activation of mono- cytes during pre-eclampsia. Factors may be derived from the MONOCYTES AND PARTURITION stressed placenta, such as anti-angiogenic factors (61), pla- Parturition is associated with an inflammatory response (45). At cental microparticles (62), or ATP (9), which are released at the end of gestation, the number of leukocytes in the uterine tissue increased amounts from the pre-eclamptic placenta. These fac- are increased (46). Also in the peripheral circulation just before tors may activate the monocytes. Also upregulation of various delivery, further phenotypical activation of monocytes in com- pro-inflammatory cytokines, such as TNFa, IL-1b, IL-18, in the parison with earlier in pregnancy has been shown (47), indicating placenta of pre-eclamptic women has been observed (63–65). On further activation of these cells just before delivery. In line with the other hand, decreased levels of the anti-inflammatory cytokine this suggestion, more recently, Vega-Sanchez et al. (48) showed IL-10 have been observed in the placenta of pre-eclamptic women differences in cytokine production of monocytes between preg- (66, 67). These increased levels of pro-inflammatory cytokines in nant women in labor and pregnant women not in labor. A role the pre-eclamptic placenta may be responsible for the increased for activated monocytes in parturition can also be deduced from data from pre-term labor, where increased expression of activation markers by monocytes has been observed compared with healthy pregnancy (49). MONOCYTES IN PRE-ECLAMPSIA It has now been well-established that during pre-eclampsia, the innate immune system is even further activated as compared with normal pregnancy (50). Activation of monocytes has been demonstrated by increased expression of inflammation associated adhesion molecules such as CD11b, ICAM-1, and CD14 (5, 32, 51, 52). However, monocytes are not only phenotypically activated, they also produced increased amounts of oxygen free radicals as compared to normal pregnancy (32) and their cytokine pro- duction also differed as compared to monocytes from normal pregnant women (38, 53–56). As for normal pregnancy, the above mentioned studies did not take into account the presence of mono- cyte subsets and monocytes are generally defined as CD14 positive. In our recent study, we observed decreased numbers of classical FIGURE 1 | Schematic overview of the placenta. The placenta consists of monocytes and an increased numbers of intermediate monocytes a fetal part and a maternal part. In the fetal part of the placenta, chorionic in women with pre-eclampsia as compared with normal preg- villi, covered with syncytiotrophoblast, bath in maternal blood of the nant women (41). Although Al-ofi et al. also showed decreased intervillous space. Direct or indirect contact (via soluble factors) of numbers of classical monocytes, in contrast to our study, they monocytes with the syncytiotrophoblast may results in monocyte activation. The maternal part of the placenta consists of decidua in which showed increased numbers of non-classical monocytes in pre- remodeled spiral arteries are present, which take maternal blood to the eclamptic women compared with healthy pregnant women (44). intervillous space. In the decidua fetal trophoblast, and maternal As explained above, this may be due to different techniques used, macrophages and NK cells are present and necessary for immune but may also be due to a different selection of patient groups regulation and spiral artery remodeling ©ilusjessy – Fotolia.com. (we exclusively included early onset pre-eclamptic women, while www.frontiersin.org June 2014 | Volume 5 | Article 298 | 3 Faas et al. Monocytes and macrophages in pregnancy and pre-eclampsia circulating levels of these cytokines in pre-eclamptic patients (68, be similar in rat and human pregnancy. Therefore pregnancy- 69). These cytokines may also activate the monocytes. Since mono- induced changes in the immune response may also be similar to cytes themselves are potent producers of cytokines, the activation human pregnancy. Indeed, similar phenotypical and functional of monocyte by placental factors and cytokines may in turn result activation of monocytes during the course of pregnancy have been in a vicious circle of monocytes activation and cytokine pro- observed in rats as compared with humans (75, 76). Moreover, in duction leading to persistent increased monocyte activation in accordance with human pregnancy, we found decreased numbers pre-eclampsia. of classical monocytes and increased numbers of non-classical It appears to be important for induction of pre-eclamptic signs monocytes during pregnancy in this species (41). how monocytes are activated. In pregnant rats, hypertension and Various rat models have suggested that activation of mono- proteinuria can only be induced after infusion with E coli LPS cytes, by LPS, ATP, or TNFa during pregnancy, induced pre- (70), not after infusion of LPS from Porphyromonas gingivalis (71), eclampsia-like signs (70, 77, 78). Interestingly, such pre-eclampsia- despite the fact that monocytes are activated by this LPS (72). like syndromes were only induced in pregnant rats, not in non- This may explain why certain infections, such as urinary tract pregnant rats (70, 77). The pathophysiology of the LPS and ATP infections or periodontitis, may increase the risk of pre-eclampsia, induced pre-eclampsia was characterized by a pregnancy-specific while other infections, such as CMV or malaria do not increase the inflammatory response, characterized by persistent general (75, risk for pre-eclampsia (73). Apparently, the immune response, and 76, 79) and glomerular (79, 80) inflammation, in which mono- specifically monocyte activation is different in different infections. cytes play a major role. In the ATP model, we have shown that, Differences may amongst others relate to differences in cytokine similar to human pre-eclampsia, non-classical monocytes are production between states of monocytes activation, since we have increased and activated by ATP, suggesting an important role previously shown that activation of monocytes with E coli LPS or for this subset in pre-eclampsia. Together, these animal studies P. gingivalis LPS resulted in different cytokine production (36). support the hypothesis that activation of monocytes in preg- nancy may result in pre-eclampsia-like signs, such as hypertension MONOCYTES DURING PREGNANCY AND EXPERIMENTAL and proteinuria. PRE-ECLAMPSIA IN ANIMALS Based on the above data on monocytes during pregnancy and Although it is now generally accepted that during pregnancy pre-eclampsia, we suggest that factors that arise from the healthy monocytes are activated and that they are even further activated placenta during pregnancy induce phenotypical activation of during pre-eclampsia, whether this is the cause or consequence monocytes and induce increased maturation toward non-classical of pre-eclampsia still remains to be shown. It is difficult to study monocytes. These factors may also affect endothelial cells directly the role of monocytes in pregnancy and pre-eclampsia in human (Figure 2A). During pre-eclampsia, the stressed placenta starts subjects. Therefore, animal models are needed. A good animal to produce various pro-inflammatory factors, which further acti- model to study innate immune responses in pregnancy is the vate the monocytes and further increased monocyte maturation rat. Although not completely similar, like humans, rats have a toward non-classical monocytes. Monocyte activation results in hemochorial placenta, showing deep trophoblast invasion into the monocyte cytokine production. Via a vicious circle, these cytokines uterine wall (74) indicating that fetal–maternal interactions may may further activate the monocytes themselves as well as the FIGURE 2 | Schematic overview of the role of monocytes during healthy monocytes toward non-classical monocytes (3). Numbers non-classical pregnancy (A) and pre-eclampsia (B). During healthy pregnancy, placental monocytes are increased and they may play an important role in this factors (1) activate monocytes (2) and may affect endothelial cells (2) and inflammatory process, since they are known to produce increased numbers induce increased maturation of classical monocytes toward non-classical of cytokines upon activation (4). These cytokines further activate the monocytes (3). During pre-eclampsia, more and other soluble factors are monocytes (5) as well as endothelial cells (5). This vicious circle of activation produced from the stressed placenta (1), resulting in further activation of of monocytes and endothelial cells finally results in the symptoms of monocytes and endothelial cells (2) and further maturation of classical pre-eclampsia, such as hypertension and proteinuria. Frontiers in Immunology | Inflammation June 2014 | Volume 5 | Article 298 | 4 Faas et al. Monocytes and macrophages in pregnancy and pre-eclampsia endothelial cells, finally resulting in the signs of pre-eclampsia, Although they express many markers of M2 macrophages, such such as proteinuria and hypertension (Figure 2B). as CD206, CD163, and DC-sign (100–102), they appeared not to be typical M2 macrophages, since they are not induced by Th2 DECIDUAL MACROPHAGES cytokines, such as IL4, but by M-CSF and IL-10 (102). These Macrophages are already present in the non-pregnant data are in line with the abundant presence of M-CSF and IL- endometrium, although in low numbers (81). Since their num- 10 in the decidua (103–105). The M2 phenotype is most likely bers fluctuate during the menstrual cycle (81, 82), it seems likely due to hypermethylation of genes encoding markers of classical that these are under hormonal control (83). After fertilization, the activation and hypomethylation of genes encoding markers for number of uterine macrophages increase, due to expression of non-classical activation (106). Next to the typical M2 cytokine various chemokines (84) and during pregnancy macrophages are gene expression, these decidual macrophages also showed gene abundantly present in the decidua at all times of pregnancy (85). expression for inflammatory cytokines such as IL-6 and TNFa During pregnancy, they comprise about 20–30% of all decidual (102, 107). The production of pro-inflammatory cytokines by leukocytes (86, 87). The number of decidual macrophages may decidual macrophages may also be explained by the presence of vary with gestational age being highest in the first and second two macrophage subpopulations in the early decidua (107). One trimester (88). Macrophages in the decidua are usually associ- of these subsets may be a more pro-inflammatory subset, since this ated with spiral arteries and glands as well as with extravillous subset expressed genes associated with inflammation. The other trophoblast (86, 89), but are also found in the myometrium subset, which was higher in number, expressed genes associated (85). When the presence of macrophages in the decidua was with extracellular matrix formation, networking, communication, first discovered, it was suggested that these cells were recruited and growth (107). as the result of an immune response to the semi-allogeneic fetus Apart from the putative role of M-CSF and IL-10 in induc- (90). However, it is now generally accepted that macrophages, tion of M2 macrophages in the decidua, other factors have also and other immune cells present in the decidua, are necessary been suggested to be involved in inducing/maintaining the M2 for successful implantation (85). Various studies have focused phenotype in decidual macrophages. Decidual macrophages have on specific functions of macrophages in the decidua and it been shown to express inhibitory receptors immunoglobulin like has been suggested that the decidual macrophages have various transcript (ILT)2 and ILT4 (108). These receptors can bind to roles during pregnancy, mainly in placentation (91), but they HLA-G expressed on invading extravillous trophoblast (108), may also play a role in protecting the fetus against intrauterine after which a negative signal is delivered to the macrophages, infection (92). resulting in tolerance to the trophoblast and the induction of anti-inflammatory cytokines. It has also been suggested that the DECIDUAL MACROPHAGES IN EARLY PREGNANCY engulfment of the apoptotic cells induced an immunosuppressive Most of the studies on macrophages in the decidua have been per- and anti-inflammatory phenotype of the macrophages (97). Not formed in early pregnancy. At this time of pregnancy, macrophages only the phagocytosis of apoptotic cells, but also the phagocyto- are located near the spiral arteries during trophoblast invasion and sis of trophoblast cell debris at the maternal–fetal interface may spiral artery remodeling (86, 89). The role of macrophages in spiral be associated with the M2 phenotype of macrophages (109–111). artery remodeling was further emphasized by the fact that they are In addition, as it has been suggested that non-classical mono- present even before the presence of extravillous trophoblast (93). cytes preferentially differentiate into M2 macrophages (20), it At that time, disruption and disorganization of vascular smooth may be speculated that the increased numbers of non-classical muscle cells and endothelial cells was also observed (93). This monocytes in the circulation during pregnancy (41), results in suggests that macrophages may be important in the very early increased invasion of these cells into the decidua to become M2 phases of spiral artery remodeling, preparing the spiral arteries macrophages. for further remodeling by trophoblast cells (93). Their suggested role in vascular remodeling is in accordance with the findings DECIDUAL MACROPHAGES IN LATE PREGNANCY of production of factors associated with angiogenesis and tissue Macrophages are present in the decidua throughout pregnancy remodeling by these cells (94, 95). Indeed macrophages, which until the end of pregnancy, although their numbers may decrease at were MMP 9 positive, and which were shown to have phago- the end of pregnancy (88). The exact role of decidual macrophages cytotic capacities were found to infiltrate spiral arteries during at the end of pregnancy remains to be established, it seems, remodeling (96). Macrophages have also been shown to be impor- however, likely that they are still involved in immunoregu- tant for clearance of apoptotic cells in the decidua (97). Apoptosis lation and clearance of apoptotic cells. Indeed, many of the is an important process during spiral artery remodeling and tro- macrophages present in the decidua at the end of pregnancy, phoblast invasion. During these processes, apoptotic trophoblast appeared to be M2 macrophages (112). The potential protective cells (98) as well apoptotic cells in the vascular wall that is being effect of M2 macrophages for the fetus was recently shown by remodeled have been observed (93). By engulfment of the apop- van Schonkeren et al., who showed the presence of an inflam- totic cells, macrophages prevent the release of pro-inflammatory matory lesion in placentae from women who underwent egg substances from the apoptotic cells into the decidua [reviewed in donation (113). This lesion consisted of maternal cells, express- Ref. (97)]. ing high levels of CD14 and CD163, suggesting the presence Decidual macrophages have mainly been classified as M2- of M2 macrophages. These lesions appeared to protect against like macrophages, i.e., immunomodulatory macrophages (99). pre-eclampsia (113). www.frontiersin.org June 2014 | Volume 5 | Article 298 | 5 Faas et al. Monocytes and macrophages in pregnancy and pre-eclampsia DECIDUAL MACROPHAGES IN PRE-ECLAMPSIA (120, 121). The presence of macrophages in the spiral arteries Preeclampsia is associated with defective trophoblast invasion and may be associated with the development of acute artherosis (120). spiral artery remodeling: while in healthy pregnancy, spiral artery Acute artherosis is a process mainly seen in poorly remodeled spi- remodeling extends into the myometrium, in pre-eclampsia, spiral ral arteries at the end of pregnancy, characterized by the presence artery remodeling can only be found in the decidua (3). Unfor- of subendothelial CD68 positive foam cells (123). Its presence is tunately, not very many studies focused on macrophages in the associated with adverse fetal and maternal outcome (124). decidua in pre-eclampsia. Most of the studies in pre-eclampsia The question remains whether the increased presence of were obviously performed after delivery of the placenta. Some macrophages in the decidua of pre-eclamptic women is the of the studies reported decreased numbers of macrophages in cause or the result of pre-eclampsia. This question is difficult the decidua of pre-eclamptic patients (114, 115). Most of the to answer, due to the difficulties of obtaining material from studies, however, found increased numbers of macrophages in early decidua of women who later in pregnancy developed pre- pre-eclamptic patients (112, 116–118). These data may not neces- eclampsia. However, recently we have shown that in early decidua sarily be conflicting, since not only different methods were used from women who later developed pregnancy-induced hyperten- (Williams and Burk performed a flow cytometric study, while sion (PIH) (including pre-eclampsia) CD68 mRNA expression was the other studies were immunohistochemical studies), also dif- increased (125), suggesting increased numbers of macrophages ferent antibodies were used. Increased numbers of macrophages in the early decidua of women who later develop hyperten- in the decidua of pre-eclamptic patients appears to be in line with sion in pregnancy. Moreover, the CD206/CD68 mRNA ratio increased presence of macrophage chemotactic factors, such as was decreased in PIH women, suggesting that decreased num- M-CSF, IL-8, and MCP-1 (119–121) in pre-eclamptic patients. bers of M2 macrophages are present in the decidua of women Not only numbers of macrophages were found to be different in who later develop pregnancy-induced hypertension (125). The pre-eclamptic patients, macrophages may also be differently acti- increased numbers of macrophages, with decreased numbers of vated in pre-eclampsia (120–122). This may be in line with the M2 macrophages may thus already be present before the onset pre- presence of increased pro-inflammatory cytokines (63–65) and eclampsia and therefore suggest a role for macrophages in defec- decreased anti-inflammatory cytokines in the placenta of pre- tive trophoblast invasion and spiral artery remodeling. Recent eclamptic women (66, 67). More recently, it has been shown that in vitro data showed that macrophages migrate toward invading in the decidua of pre-eclamptic women decreased numbers of M2 trophoblast (126), while other groups have shown that activated macrophages are present (112). Differences in macrophage num- macrophages in vitro are able to inhibit trophoblast invasion and bers may be regional, since increased numbers of macrophages spiral artery remodeling (127, 128). In vivo, data have shown that were found around the spiral arteries of pre-eclamptic patients there is a reciprocal presence of trophoblast cells and macrophages FIGURE 3 | Schematic overview of the role of decidual macrophages in and tissue remodeling (such as MMP and VEGF). They also play a role in pregnancy (A) and pre-eclampsia (B). During normal pregnancy, M2-like immunomodulation, for instance by producing IL-10. During pre-eclampsia, macrophages are present around spiral arteries and play a role in remodeling increased numbers of M1-like macrophages are found. They may produce of these arteries by producing various factors associated with angiogenesis pro-inflammatory cytokines, such as TNFa, IL-1b, or IL-18. Frontiers in Immunology | Inflammation June 2014 | Volume 5 | Article 298 | 6 Faas et al. Monocytes and macrophages in pregnancy and pre-eclampsia in the spiral arteries of both healthy and pre-eclamptic women (121). Therefore the increased numbers of macrophages in and around spiral arteries of pre-eclamptic women (121) may inhibit spiral artery remodeling. Since it is difficult to study the role of macrophages in pre- eclampsia in humans, animal models may help in understanding critical questions. Studying whether trophoblast invasion and spiral artery remodeling is associated with macrophages in ani- mal models for pre-eclampsia may shed light on the question whether increased numbers of macrophages in the decidua are the cause or the result of pre-eclampsia. In an animal model for pre-eclampsia induced by multiple doses of LPS in pregnant rats, decreased trophoblast invasion and spiral artery remodeling after LPS was associated with increased numbers of macrophages. We studied this subject and showed increased invasion of acti- vated macrophages in the mesometrial triangle (the equivalent of the placental bed in humans) before defective trophoblast inva- sion and spiral artery remodeling (129). This appears to be in line with the sparse human data and suggests a role for activated macrophages in the pathophysiology of pre-eclampsia. M2-like macrophages are thus abundantly present in the decidua of healthy pregnant women. They are observed in the presence of spiral arteries and extravillous trophoblast cells and may play a role in spiral artery remodeling by producing factors associated with angiogenesis and tissue remodeling, such as MMPs and VEGF (Figure 3A). During pre-eclampsia, increased num- bers of decidual macrophages are observed, which may be of the M1 phenotype and therefore produce pro-inflammatory cytokines FIGURE 4 | Summary of monocytes and macrophages in (Figure 3B). These activated macrophages may affect spiral arter- pregnancy and pre-eclampsia. In healthy pregnancy, soluble factors ies and may induce acute artherosis, affecting the placental blood from the villous trophoblast activate circulating monocytes, induce circulation. maturation of classical monocytes toward non-classical monocytes and affect endothelial cells. Non-classical monocytes will invade into the decidua to become M2-like macrophages to support healthy SUMMARY placentation and immunomodulation. During pre-eclampsia, decreased Monocytes and macrophages play important roles in pregnancy remodeling of the spiral arteries will results in a stressed placenta, and pre-eclampsia. Monocyte activation and increased numbers which produces increased amounts or different soluble factors as of non-classical monocytes, is important for normal pregnancy. compared with healthy pregnancy. The soluble factors will further Monocyte derived macrophages, especially M2-like macrophages activate the monocytes, induce further maturation of classical monocytes toward non-classical monocytes and activate endothelial (which may be derived from non-classical monocytes) in the cells. Activated monocytes, by f.i. producing cytokines, further affect decidua in healthy pregnancy play an important role in blastocyst monocytes and endothelial cells. This vicious circle of monocyte and implantation, trophoblast invasion, and spiral artery remodeling endothelial cell activation results in the maternal symptoms of as well as in defense against infection and in immunomodula- pre-eclampsia, i.e., hypertension and proteinuria. Moreover, activated tion (Figure 4). During pre-eclampsia, decreased spiral artery classical and non-classical monocytes may invade into the decidua to develop into M1-like and M2-like macrophages, resulting in increased remodeling results in increased production of soluble factors numbers of M1-like macrophages in the pre-eclamptic decidua. The (or different factors), inducing further activation of both classi- M1-like macrophages may affect the spiral arteries resulting in f.i. acute cal and non-classical monocytes and further maturation toward atherosis, thereby further affecting the placental blood circulation. non-classical monocytes. These placental factors as well as the activated monocytes also induce activation of endothelial cells. Activated monocytes (both classical and non-classical monocytes) may invade into the decidua, resulting in increased numbers of decidual macrophages do also play a role in the aberrant spiral M1-like macrophages in the decidua of pre-eclamptic women artery remodeling early in pregnancy. The question thus remains (Figure 4). The M1-like macrophages may affect the spiral arteries, as to what induces the aberrant spiral artery remodeling? Future by for instance inducing acute artherosis. This may further affect studies should therefore not only focus on the three monocyte sub- the placental blood circulation and stress the placenta. sets in pregnancy and pre-eclampsia, but also on the relationship Unfortunately, most studies on monocytes and macrophages between the circulating monocyte subsets and macrophages in the in pre-eclampsia have been performed during pre-eclampsia. decidua. Moreover, since data on macrophages in the decidua in Although we do believe that monocytes and decidual macrophages and before pre-eclampsia are relatively scarce future studies should do play a role in inducing the maternal symptoms of pre- therefore also focus on macrophage function and phenotype in eclampsia, it is relatively unknown whether monocytes and and before pre-eclampsia. www.frontiersin.org June 2014 | Volume 5 | Article 298 | 7 Faas et al. Monocytes and macrophages in pregnancy and pre-eclampsia REFERENCES 23. Veenstra van Nieuwenhoven AL, Bouman A, Moes H, Heineman MJ, de Leij LF, 1. Steegers EA, von Dadelszen P, Duvekot JJ, Pijnenborg R. Pre-eclampsia. Lancet Santema J, et al. Cytokine production in natural killer cells and lymphocytes in (2010) 376(9741):631–44. doi:10.1016/S0140- 6736(10)60279- 6 pregnant women compared with women in the follicular phase of the ovarian 2. Duley L. The global impact of pre-eclampsia and eclampsia. Semin Perinatol cycle. Fertil Steril (2002) 77(5):1032–7. doi:10.1016/S0015- 0282(02)02976- X (2009) 33(3):130–7. doi:10.1053/j.semperi.2009.02.010 24. Saito S, Sakai M, Sasaki Y, Tanebe K, Tsuda H, Michimata T. Quantitative 3. Redman CW, Sargent IL. Placental stress and pre-eclampsia: a revised view. analysis of peripheral blood Th0, Th1, Th2 and the Th1:Th2 cell ratio dur- Placenta (2009) 30(Suppl A):S38–42. doi:10.1016/j.placenta.2008.11.021 ing normal pregnancy and preeclampsia. Clin Exp Immunol (1999) 117:550–5. 4. Sacks GP, Sargent IL, Redman CWG. An innate view of human pregnancy. doi:10.1046/j.1365- 2249.1999.00997.x Immunol Today (1999) 20(3):114–8. doi:10.1016/S0167- 5699(98)01393- 0 25. Borzychowski AM, Croy BA, Chan WL, Redman CW, Sargent IL. Changes in 5. Mellembakken JR, Aukrust P, Olafsen MK, Ueland T, Hestdal K, Videm V. systemic type 1 and type 2 immunity in normal pregnancy and pre-eclampsia Activation of leukocytes during the uteroplacental passage in preeclampsia. may be mediated by natural killer cells. Eur J Immunol (2005) 35(10):3054–63. Hypertension (2002) 39(1):155–60. doi:10.1161/hy0102.100778 doi:10.1002/eji.200425929 6. Hung TH, Charnock-Jones DS, Skepper JN, Burton GJ. Secretion of tumor 26. Ernerudh J, Berg G, Mjösberg J. Regulatory T helper cells in pregnancy and necrosis factor-alpha from human placental tissues induced by hypoxia- their roles in systemic versus local immune tolerance. Am J Reprod Immunol reoxygenation causes endothelial cell activation in vitro: a potential medi- (2011) 66(Suppl 1):31–43. doi:10.1111/j.1600- 0897.2011.01049.x ator of the inflammatory response in preeclampsia. Am J Pathol (2004) 27. Saito S, Nakashima A, Shima T, Ito M. Th1/Th2/Th17 and regulatory T- 164(3):1049–61. doi:10.1016/S0002- 9440(10)63192- 6 cell paradigm in pregnancy. Am J Reprod Immunol (2010) 63(6):601–10. 7. Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, et al. Circu- doi:10.1111/j.1600- 0897.2010.00852.x lating angiogenic factors and the risk of preeclampsia. N Engl J Med (2004) 28. Siegel I, Gleicher N. Changes in peripheral mononuclear cells in pregnancy. 350(7):672–83. doi:10.1056/NEJMoa031884 Am J Reprod Immunol (1981) 1(3):154–5. 8. Germain SJ, Sacks GP, Soorana SR, Sargent IL, Redman CW. Systemic inflam- 29. Kuhnert M, Strohmeier R, Stegmuller M, Halberstadt E. Changes in lympho- matory priming in normal pregnancy and preeclampsia: the role of circu- cyte subsets during normal pregnancy. Obstet Gynecol (1998) 76:147–51. lating syncytiotrophoblast microparticles. J Immunol (2007) 178(9):5949–56. 30. Veenstra van Nieuwenhoven AL, Bouman A, Moes H, Heineman MJ, de Leij doi:10.4049/jimmunol.178.9.5949 FMLH, Santema J, et al. Endotoxin-induced cytokine production of mono- 9. Spaans F, Vos PD, Bakker WW, van Goor H, Faas MM. Danger signals from cytes of third trimester pregnant women compared to women in the follic- ATP and adenosine in pregnancy and preeclampsia. Hypertension (2014) ular phase of the menstrual cycle. Am J Obstet Gynecol (2003) 188:1073–7. 63(6):1154–60. doi:10.1161/HYPERTENSIONAHA.114.03240 doi:10.1067/mob.2003.263 10. Wallace AE, Fraser R, Cartwright JE. Extravillous trophoblast and decidual 31. Macey MG, McCarthy DA, Vordermeier S, Newland AC, Brown KA. Effects of natural killer cells: a remodelling partnership. Hum Reprod Update (2012) cell purification methods on CD11b and L-selectin expression as well as adher- 18(4):458–71. doi:10.1093/humupd/dms015 ence and activation of leukocytes. J Immunol Methods (1995) 181(2):211–9. 11. Svensson-Arvelund J, Ernerudh J, Buse E, Cline JM, Haeger JD, Dixon doi:10.1016/0022- 1759(95)00003- S D, et al. The placenta in toxicology. Part II: systemic and local immune 32. Sacks GP, Studena K, Sargent IL, Redman CWG. Normal pregnancy and adaptations in pregnancy. Toxicol Pathol (2014) 42(2):327–38. doi:10.1177/ preeclampsia both produce inflammatory changes in peripheral blood leuko- 0192623313482205 cytes akin to those of sepsis. Am J Obstet Gynecol (1998) 179:80–6. doi:10.1016/ 12. Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev S0002- 9378(98)70254- 6 Immunol (2005) 5(12):953–64. doi:10.1038/nri1733 33. Naccasha N, Gervasi MT, Chaiworapongsa T, Berman S, Yoon BH, Maymon 13. Ziegler-Heitbrock L, Ancuta P, Crowe S, Dalod M, Grau V, Hart DN, et al. E, et al. Phenotypic and metabolic characteristics of monocytes and granulo- Nomenclature of monocytes and dendritic cells in blood. Blood (2010) cytes in normal pregnancy and maternal infection. Am J Obstet Gynecol (2001) 116(16):e74–80. doi:10.1182/blood- 2010- 02- 258558 185(5):1118–23. doi:10.1067/mob.2001.117682 14. Sunderkötter C, Nikolic T, Dillon MJ, Van Rooijen N, Stehling M, Drevets 34. Luppi P, Haluszczak C, Betters D, Richard CAH, Trucco M, DeLoia JA. Mono- DA, et al. Subpopulations of mouse blood monocytes differ in matura- cytes are progressively activated in the circulation of pregnant women. J Leukoc tion stage and inflammatory response. J Immunol (2004) 172(7):4410–7. Biol (2002) 72(5):874–84. doi:10.4049/jimmunol.172.7.4410 35. Luppi P, Haluszczak C, Trucco M, DeLoia JA. Normal pregnancy is asso- 15. Auffray C, Fogg D, Garfa M, Elain G, Join-Lambert O, Kayal S, et al. Monitor- ciated with peripheral leukocyte activation. Am J Reprod Immunol (2002) ing of blood vessels and tissues by a population of monocytes with patrolling 47(2):72–81. doi:10.1034/j.1600- 0897.2002.1o041.x behavior. Science (2007) 317(5838):666–70. doi:10.1126/science.1142883 36. Faas MM, Kunnen A, Dekker DC, Harmsen HJ, Aarnoudse JG, Abbas F, et al. 16. Fingerle G, Pforte A, Passlick B, Blumenstein M, Strobel M, Ziegler-Heitbrock Porphyromonas gingivalis and E-coli induce different cytokine production pat- HW. The novel subset of CD14+/CD16+ blood monocytes is expanded in terns in pregnant women. PLoS One (2014) 9(1):e86355. doi:10.1371/journal. sepsis patients. Blood (1993) 82(10):3170–6. pone.0086355 17. Zimmermann HW, Seidler S, Nattermann J, Gassler N, Hellerbrand C, Zer- 37. Beckmann I, Efraim SB, Vervoort M, Visser W, Wallenburg HC. Tumor necro- necke A, et al. Functional contribution of elevated circulating and hepatic non- sis factor-alpha in whole blood cultures of preeclamptic patients and healthy classical CD14CD16 monocytes to inflammation and human liver fibrosis. pregnant and nonpregnant women. Hypertens Pregnancy (2004) 23(3):319–29. PLoS One (2010) 5(6):e11049. doi:10.1371/journal.pone.0011049 doi:10.1081/PRG- 200030334 18. Mantovani A, Biswas SK, Galdiero MR, Sica A, Locati M. Macrophage plas- 38. Sacks GP, Redman CWG, Sargent IL. Monocytes are primed to produce the ticity and polarization in tissue repair and remodelling. J Pathol (2013) Th1 type cytokine IL-12 in normal human pregnancy: an intracellular flow 229(2):176–85. doi:10.1002/path.4133 cytometric analysis of peripheral blood mononuclear cells. Clin Exp Immunol 19. Porcheray F, Viaud S, Rimaniol AC, Léone C, Samah B, Dereuddre-Bosquet N, (2003) 131(3):490–7. doi:10.1046/j.1365- 2249.2003.02082.x et al. Macrophage activation switching: an asset for the resolution of inflam- 39. Faas MM, Moes H, Fijen JW, Muller Kobold AC, Tulleken JE, Zijlstra JG. mation. Clin Exp Immunol (2005) 142(3):481–9. doi:10.1111/j.365- 2249.2005. Monocyte intracellular cytokine production during human endotoxemia with 02934.x or without a second in vitro LPS challenge: effect of RWJ067657, a p36 20. Yang J, Zhang L, Yu C, Yang XF, Wang H. Monocyte and macrophage differ- MAP-kinase inhibitor, on LPS-hyporesponsiveness. Clin Exp Immunol (2002) entiation: circulation inflammatory monocyte as biomarker for inflammatory 127:337–43. doi:10.1046/j.1365- 2249.2002.01765.x diseases. Biomark Res (2014) 2(1):1. doi:10.1186/2050- 7771- 2- 1 40. Chen J, Ivashkiv LB. IFN-g abrogates endotoxin tolerance by facilitating toll- 21. Spahn JH, Kreisel D. Monocytes in sterile inflammation: recruitment and func- like receptor-induced chromatin remodeling. Proc Natl Acad Sci U S A (2010) tional consequences. Arch Immunol Ther Exp (Warsz) (2013) 62(3):187–94. 107(45):19438–43. doi:10.1073/pnas.1007816107 doi:10.1007/s00005- 013- 0267- 5 41. Melgert BN, Spaans F, Borghuis T, Klok PA, Groen B, Bolt A, et al. Pregnancy 22. Wegmann TG, Lin H, Guilbert L, Mosmann TR. Bidirectional cytokine and preeclampsia affect monocyte subsets in humans and rats. PLoS One (2012) interactions in the maternal-fetal relationship: is successful pregnancy a Th2 7(9):e45229. doi:10.1371/journal.pone.0045229 phenomenon? Immunol Today (1993) 14:353–6. doi:10.1016/0167- 5699(93) 42. Rossol M, Kraus S, Pierer M, Baerwald C, Wagner U. The CD14(bright) 90235- D CD16+ monocyte subset is expanded in rheumatoid arthritis and promotes Frontiers in Immunology | Inflammation June 2014 | Volume 5 | Article 298 | 8 Faas et al. Monocytes and macrophages in pregnancy and pre-eclampsia expansion of the Th17 cell population. Arthritis Rheum (2012) 64(3):671–7. 61. Steinberg G, Khankin EV, Karumanchi SA. Angiogenic factors and preeclamp- doi:10.1002/art.33418 sia. Thromb Res (2009) 123(Suppl 2):S93–9. doi:10.1016/S0049- 3848(09) 43. Moniuszko M, Bodzenta-Lukaszyk A, Kowal K, Lenczewska D, Dabrowska M. 70020- 9 Enhanced frequencies of CD14++CD16+, but not CD14+CD16+, periph- 62. Redman CW, Sargent IL. Placental debris, oxidative stress and pre-eclampsia. eral blood monocytes in severe asthmatic patients. Clin Immunol (2009) Placenta (2000) 21(7):597–602. doi:10.1053/plac.2000.0560 130(3):338–46. doi:10.1016/j.clim.2008.09.011 63. Pang ZJ, Xing FQ. Comparative study on the expression of cytokine – receptor 44. Al-ofi E, Coffelt SB, Anumba DO. Monocyte subpopulations from pre- genes in normal and preeclamptic human placentas using DNA microarrays. eclamptic patients are abnormally skewed and exhibit exaggerated responses to J Perinat Med (2003) 31(2):153–62. doi:10.1515/JPM.2003.021 toll-like receptor ligands. PLoS One (2012) 7(7):e42217. doi:10.1371/journal. 64. Benyo DF, Smarason A, Redman CW, Sims C, Conrad KP. Expression of pone.0042217 inflammatory cytokines in placentas from women with preeclampsia. J Clin 45. Kelly RW. Inflammatory mediators and parturition. Rev Reprod (1996) Endocrinol Metab (2001) 86(6):2505–12. doi:10.1210/jc.86.6.2505 1(2):89–96. 65. Wang Y, Walsh SW. TNF alpha concentrations and mRNA expression are 46. Bokström H, Brännström M, Alexandersson M, Norström A. Leukocyte sub- increased in preeclamptic placentas. J Reprod Immunol (1996) 32(2):157–69. populations in the human uterine cervical stroma at early and term pregnancy. doi:10.1016/S0165- 0378(96)00998- 9 Hum Reprod (1997) 12(3):586–90. doi:10.1093/humrep/12.3.586 66. Hennessy A, Pilmore HL, Simmons LA, Painter DM. A deficiency of placental 47. Luppi P, Irwin TE, Simhan H, Deloia JA. CD11b Expression on circulating IL-10 in preeclampsia. J Immunol (1999) 163(6):3491–5. leukocytes increases in preparation for parturition. Am J Reprod Immunol 67. Rein DT, Breidenbach M, Hönscheid B, Friebe-Hoffmann U, Engel H, Göhring (2004) 52(5):323–9. doi:10.1111/j.1600- 0897.2004.00229.x UJ, et al. Preeclamptic women are deficient of interleukin-10 as assessed by 48. Vega-Sanchez R, Gomez-Lopez N, Flores-Pliego A, Clemente-Galvan S, cytokine release of trophoblast cells in vitro. Cytokine (2003) 23(4–5):119–25. Estrada-Gutierrez G, Zentella-Dehesa A, et al. Placental blood leukocytes are doi:10.1016/S1043- 4666(03)00220- 5 functional and phenotypically different than peripheral leukocytes during 68. Vince GS, Starkey PM, Austgulen R, Kwaitkowski D, Redman CWG. human labor. J Reprod Immunol (2010) 84(1):100–10. doi:10.1016/j.jri.2009. Interleukin-6, tumour necrosis factor and soluble tumour necrosis factor recep- 08.002 tors in women with pre-eclampsia. Br J Obstet Gynaecol (1995) 102:20–5. 49. Gervasi MT, Chaiworapongsa T, Naccasha N, Blackwell S, Yoon BH, Maymon doi:10.1111/j.1471- 0528.1995.tb09020.x E, et al. Phenotypic and metabolic characteristics of maternal monocytes and 69. Conrad KP, Miles TM, Benyo DF. Circulating levels of immunoreactive granulocytes in preterm labor with intact membranes. Am J Obstet Gynecol cytokines in women with preeclampsia. Am J Reprod Immunol (1998) (2001) 185(5):1124–9. doi:10.1067/mob.2001.117311 40(2):102–11. doi:10.1111/j.1600- 0897.1998.tb00398.x 50. Borzychowski AM, Sargent IL, Redman CW. Inflammation and pre-eclampsia. 70. Faas MM, Schuiling GA, Baller JFW, Visscher CA, Bakker WW. A new animal Semin Fetal Neonatal Med (2006) 11(5):309–16. doi:10.1016/j.siny.2006.04.001 model for human pre-eclampsia: ultralow dose endotoxin infusion in preg- 51. Gervasi MT, Chaiworapongsa T, Pacora P, Naccasha N, Yoon BH, May- nant rats. Am J Obstet Gynecol (1994) 171:158–64. doi:10.1016/0002- 9378(94) mon E, et al. Phenotypic and metabolic characteristics of monocytes and 90463- 4 granulocytes in preeclampsia. Am J Obstet Gynecol (2001) 185(4):792–7. 71. Kunnen A, Van Pampus MG, Aarnoudse JG, van der Schans CP, Abbas F, Faas doi:10.1067/mob.2001.117311 MM. The effect of Porphyromonas gingivalis lipopolysaccharide on pregnancy 52. Luppi P, Tse H, Lain KY, Markovic N, Piganelli JD, DeLoia JA. Preeclampsia acti- in the rat. Oral Dis (2013). doi:10.1111/odi.12177 vates circulating immune cells with engagement of the NF-kappaB pathway. Am 72. Kunnen A, Dekker DC, van Pampus MG, Harmsen HJ, Aarnoudse JG, Abbas J Reprod Immunol (2006) 56(2):135–44. doi:10.1111/j.1600- 0897.2006.00386. F, et al. Cytokine production induced by non-encapsulated and encapsu- x lated Porphyromonas gingivalis strains. Arch Oral Biol (2012) 57(11):1558–66. 53. Sakai M, Tsuda H, Tanebe K, Sasaki Y, Saito S. Interleukin-12 secretion by doi:10.1016/j.archoralbio.2012.07.013 peripheral blood mononuclear cells is decreased in normal pregnant sub- 73. Conde-Agudelo A, Villar J, Lindheimer M. Maternal infection and risk of jects and increased in preeclamptic patients. Am J Reprod Immunol (2002) preeclampsia: systematic review and metaanalysis. Am J Obstet Gynecol (2008) 47(2):91–7. doi:10.1034/j.1600- 0897.2002.1o020.x 198(1):7–22. doi:10.1016/j.ajog.2007.07.040 54. Peraçoli JC, Rudge MV, Peraçoli MT. Tumor necrosis factor-alpha in gestation 74. Soares MJ, Chakraborty D, Karim Rumi MA, Konno T, Renaud SJ. Rat placen- and puerperium of women with gestational hypertension and pre-eclampsia. tation: an experimental model for investigating the hemochorial maternal-fetal Am J Reprod Immunol (2007) 57(3):177–85. doi:10.1111/j.1600- 0897.2006. interface. Placenta (2012) 33(4):233–43. doi:10.1016/j.placenta.2011.11.026 00455.x 75. Faas MM, Schuiling GA, Linton EA, Sargent IL, Redman CW. Activation of 55. Veenstra van Nieuwenhoven AL, Moes H, Heineman MJ, Santema J, Faas MM. peripheral leukocytes in rat pregnancy and experimental preeclampsia. Am Cytokine production by monocytes, NK cells and lymphocytes is different in J Obstet Gynecol (2000) 182(2):351–7. doi:10.1016/S0002- 9378(00)70223- 7 preeclamptic patients as compared with normal pregnant women. Hypertens 76. Faas MM, Broekema M, Moes H, van der Schaaf G, Heineman MJ, de Vos P. Pregnancy (2008) 27(3):207–24. doi:10.1080/10641950701885006 Altered monocyte function in experimental preeclampsia in the rat. Am J Obstet 56. Brewster JA, Orsi NM, Gopichandran N, Ekbote UV, Cadogan E, Walker Gynecol (2004) 191(4):1192–8. doi:10.1016/j.ajog.2004.03.041 JJ. Host inflammatory response profiling in preeclampsia using an in vitro 77. Faas MM, van der Schaaf G, Borghuis T, Jongman RM, van Pampus MG, de whole blood stimulation model. Hypertens Pregnancy (2008) 27(1):1–16. Vos P, et al. Extracellular ATP induces albuminuria in pregnant rats. Nephrol doi:10.1080/10641950701826067 Dial Transplant (2010) 25(8):2468–78. doi:10.1093/ndt/gfq095 57. Sacks GP, Clover LM, Bainbridge DR, Redman CW, Sargent IL. Flow cyto- 78. LaMarca B, Speed J, Fournier L, Babcock SA, Berry H, Cockrell K, et al. metric measurement of intracellular Th1 and Th2 cytokine production by Hypertension in response to chronic reductions in uterine perfusion in preg- human villous and extravillous cytotrophoblast. Placenta (2001) 22(6):550–9. nant rats: effect of tumor necrosis factor-alpha blockade. Hypertension (2008) doi:10.1053/plac.2001.0686 52(6):1161–7. doi:10.1161/HYPERTENSIONAHA.108.120881 58. Redman CW, Tannetta DS, Dragovic RA, Gardiner C, Southcombe JH, Collett 79. Spaans F, Melgert BN, Borghuis T, Klok PA, de Vos P, Bakker WW, et al. Extra- GP, et al. Review: does size matter? Placental debris and the pathophysiology cellular adenosine triphosphate affects systemic and kidney immune cell pop- of pre-eclampsia. Placenta (2012) 33(Suppl):S48–54. doi:10.1016/j.placenta. ulations in pregnant rats. Am J Reprod Immunol (2014). doi:10.1111/aji.12267 2011.12.006 80. Faas MM, Schuiling GA, Baller JFW, Bakker WW. Glomerular inflammation 59. Bianchi DW, Zickwolf GK, Weil GJ, Sylvester S, DeMaria MA. Male fetal prog- in pregnant rats after infusion of low dose endotoxin: an immunohistological enitor cells persist in maternal blood for as long as 27 years postpartum. Proc study in experimental pre-eclampsia. Am J Pathol (1995) 147:1510–8. Natl Acad Sci U S A (1996) 93(2):705–8. doi:10.1073/pnas.93.2.705 81. Bulmer JN, Morrison L, Longfellow M, Ritson A, Pace D. Granulated lym- 60. Faas MM, van Pampus MG, Anninga ZA, Salomons J, Westra IM, Donker RB, phocytes in human endometrium: histochemical and immunohistochemical et al. Plasma from preeclamptic women activates endothelial cells via mono- studies. Hum Reprod (1991) 6(6):791–8. cyte activation in vitro. J Reprod Immunol (2010) 87(1–2):28–38. doi:10.1016/ 82. Klentzeris LD, Bulmer JN, Warren A, Morrison L, Li TC, Cooke ID. Endome- j.jri.2010.07.005 trial lymphoid tissue in the timed endometrial biopsy: morphometric and www.frontiersin.org June 2014 | Volume 5 | Article 298 | 9 Faas et al. Monocytes and macrophages in pregnancy and pre-eclampsia immunohistochemical aspects. Am J Obstet Gynecol (1992) 167(3):667–74. 104. Thaxton JE, Sharma S. Interleukin-10: a multi-faceted agent of pregnancy. doi:10.1016/S0002- 9378(11)91568- 3 Am J Reprod Immunol (2010) 63(6):482–91. doi:10.1111/j.1600- 0897.2010. 83. Hunt JS, Miller L, Platt JS. Hormonal regulation of uterine macrophages. Dev 00810.x Immunol (1998) 6(1–2):105–10. 105. Roth I, Corry DB, Locksley RM, Abrams JS, Litton MJ, Fisher SJ. Human pla- 84. Jones RL, Hannan NJ, Kaitu’u TJ, Zhang J, Salamonsen LA. Identification of cental cytotrophoblasts produce the immunosuppressive cytokine interleukin chemokines important for leukocyte recruitment to the human endometrium 10. J Exp Med (1996) 184(2):539–48. doi:10.1084/jem.184.2.539 at the times of embryo implantation and menstruation. J Clin Endocrinol Metab 106. Kim SY, Romero R, Tarca AL, Bhatti G, Kim CJ, Lee J, et al. Methylome (2004) 89(12):6155–67. doi:10.1210/jc.2004- 0507 of fetal and maternal monocytes and macrophages at the feto-maternal inter- 85. Bulmer JN, Williams PJ, Lash GE. Immune cells in the placental bed. Int J Dev face. Am J Reprod Immunol (2012) 68(1):8–27. doi:10.1111/j.1600- 0897.2012. Biol (2010) 54(2–3):281–94. doi:10.1387/ijdb.082763jb 01108.x 86. Bulmer JN, Morrison L, Smith JC. Expression of class II MHC gene prod- 107. Houser BL, Tilburgs T, Hill J, Nicotra ML, Strominger JL. Two unique ucts by macrophages in human uteroplacental tissue. Immunology (1988) human decidual macrophage populations. J Immunol (2011) 186(4):2633–42. 63(4):707–14. doi:10.4049/jimmunol.1003153 87. Lessin DL, Hunt JS, King CR, Wood GW. Antigen expression by cells near the 108. Petroff MG, Sedlmayr P, Azzola D, Hunt JS. Decidual macrophages are poten- maternal-fetal interface. Am J Reprod Immunol Microbiol (1988) 16(1):1–7. tially susceptible to inhibition by class Ia and class Ib HLA molecules. J Reprod 88. Williams PJ, Searle RF, Robson SC, Innes BA, Bulmer JN. Decidual leuko- Immunol (2002) 56(1–2):3–17. doi:10.1016/S0165- 0378(02)00024- 4 cyte populations in early to late gestation normal human pregnancy. J Reprod 109. Abumaree MH, Chamley LW, Badri M, El-Muzaini MF. Trophoblast debris Immunol (2009) 82(1):24–31. doi:10.1016/j.jri.2009.08.001 modulates the expression of immune proteins in macrophages: a key to mater- 89. Bulmer JN, Johnson PM. Macrophage populations in the human placenta and nal tolerance of the fetal allograft? J Reprod Immunol (2012) 94(2):131–41. amniochorion. Clin Exp Immunol (1984) 57(2):393–403. doi:10.1016/j.jri.2012.03.488 90. Tafuri A, Alferink J, Moller P, Hammerling GJ, Arnold B. T cell awareness 110. Fadok VA, Chimini G. The phagocytosis of apoptotic cells. Semin Immunol of paternal alloantigens during pregnancy. Science (1995) 270(5236):630–3. (2001) 13(6):365–72. doi:10.1006/smim.2001.0333 doi:10.1126/science.270.5236.630 111. Van Ginderachter JA, Movahedi K, Hassanzadeh Ghassabeh G, Meerschaut S, 91. Renaud SJ, Graham CH. The role of macrophages in utero-placental inter- Beschin A, Raes G, et al. Classical and alternative activation of mononuclear actions during normal and pathological pregnancy. Immunol Invest (2008) phagocytes: picking the best of both worlds for tumor promotion. Immunobi- 37(5):535–64. doi:10.1080/08820130802191375 ology (2006) 211(6–8):487–501. doi:10.1016/j.imbio.2006.06.002 92. Singh U, Nicholson G, Urban BC, Sargent IL, Kishore U, Bernal AL. Immuno- 112. Schonkeren D, van der Hoorn ML, Khedoe P, Swings G, van Beelen E, Claas logical properties of human decidual macrophages – a possible role in F, et al. Differential distribution and phenotype of decidual macrophages in intrauterine immunity. Reproduction (2005) 129(5):631–7. doi:10.1530/rep.1. preeclamptic versus control pregnancies. Am J Pathol (2011) 178(2):709–17. 00331 doi:10.1016/j.ajpath.2010.10.011 93. Smith SD, Dunk CE, Aplin JD, Harris LK, Jones RL. Evidence for immune cell 113. Schonkeren D, Swings G, Roberts D, Claas F, de Heer E, Scherjon S. Pregnancy involvement in decidual spiral arteriole remodeling in early human pregnancy. close to the edge: an immunosuppressive infiltrate in the chorionic plate of pla- Am J Pathol (2009) 174(5):1959–71. doi:10.2353/ajpath.2009.080995 centas from uncomplicated egg cell donation. PLoS One (2012) 7(3):e32347. 94. Engert S, Rieger L, Kapp M, Becker JC, Dietl J, Kämmerer U. Profiling doi:10.1371/journal.pone.0032347 chemokines, cytokines and growth factors in human early pregnancy decidua 114. Williams PJ, Bulmer JN, Searle RF, Innes BA, Robson SC. Altered decidual by protein array. Am J Reprod Immunol (2007) 58(2):129–37. doi:10.1111/j. leukocyte populations in the placental bed in pre-eclampsia and foetal growth 1600- 0897.2007.00498.x restriction: a comparison with late normal pregnancy. Reproduction (2009) 95. Gustafsson C, Mjösberg J, Matussek A, Geffers R, Matthiesen L, Berg G, 138(1):177–84. doi:10.1530/REP- 09- 0007 et al. Gene expression profiling of human decidual macrophages: evidence 115. Bürk MR, Troeger C, Brinkhaus R, Holzgreve W, Hahn S. Severely reduced for immunosuppressive phenotype. PLoS One (2008) 3(4):e2078. doi:10.1371/ presence of tissue macrophages in the basal plate of pre-eclamptic placentae. journal.pone.0002078 Placenta (2001) 22(4):309–16. doi:10.1053/plac.2001.0624 96. Hazan AD, Smith SD, Jones RL, Whittle W, Lye SJ, Dunk CE. Vascular-leukocyte 116. Reister F, Frank HG, Kingdom JC, Heyl W, Kaufmann P, Rath W, et al. interactions: mechanisms of human decidual spiral artery remodeling in vitro. Macrophage-induced apoptosis limits endovascular trophoblast invasion in Am J Pathol (2010) 177(2):1017–30. doi:10.2353/ajpath.2010.091105 the uterine wall of preeclamptic women. Lab Invest (2001) 81(8):1143–52. 97. Abrahams VM, Kim YM, Straszewski SL, Romero R, Mor G. Macrophages doi:10.1038/labinvest.3780326 and apoptotic cell clearance during pregnancy. Am J Reprod Immunol (2004) 117. Wilczynski JR, Tchórzewski H, Banasik M, Głowacka E, Wieczorek A, Lewkow- 51(4):275–82. doi:10.1111/j.1600- 0897.2004.00156.x icz P, et al. Lymphocyte subset distribution and cytokine secretion in third 98. Piacentini M, Autuori F. Immunohistochemical localization of tissue transglut- trimester decidua in normal pregnancy and preeclampsia. Eur J Obstet Gynecol aminase and Bcl-2 in rat uterine tissues during embryo implantation and post- Reprod Biol (2003) 109(1):8–15. doi:10.1016/S0301- 2115(02)00350- 0 partum involution. Differentiation (1994) 57(1):51–61. doi:10.1046/j.1432- 118. Kim JS, Romero R, Cushenberry E, Kim YM, Erez O, Nien JK, et al. Distribu- 0436.1994.5710051.x tion of CD14+ and CD68+ macrophages in the placental bed and basal plate of 99. Cupurdija K, Azzola D, Hainz U, Gratchev A, Heitger A, Takikawa O, women with preeclampsia and preterm labor. Placenta (2007) 28(5–6):571–6. et al. Macrophages of human first trimester decidua express markers asso- doi:10.1016/j.placenta.2006.07.007 ciated to alternative activation. Am J Reprod Immunol (2004) 51(2):117–22. 119. Hayashi M, Hoshimoto K, Ohkura T, Inaba N. Increased levels of doi:10.1046/j.8755- 8920.2003.00128.x macrophage colony-stimulating factor in the placenta and blood in preeclamp- 100. Kämmerer U, Eggert AO, Kapp M, McLellan AD, Geijtenbeek TB, Dietl J, et al. sia. Am J Reprod Immunol (2002) 47(1):19–24. doi:10.1034/j.1600- 0897.2002. Unique appearance of proliferating antigen-presenting cells expressing DC- 1o035.x SIGN (CD209) in the decidua of early human pregnancy. Am J Pathol (2003) 120. Katabuchi H, Yih S, Ohba T, Matsui K, Takahashi K, Takeya M, et al. Character- 162(3):887–96. doi:10.1016/S00002- 9440(10)63884- 9 ization of macrophages in the decidual atherotic spiral artery with special ref- 101. Laskarin G, Cupurdija K, Tokmadzic VS, Dorcic D, Dupor J, Juretic K, et al. The erence to the cytology of foam cells. Med Electron Microsc (2003) 36(4):253–62. presence of functional mannose receptor on macrophages at the maternal-fetal doi:10.1007/s00795- 003- 0223- 2 interface. Hum Reprod (2005) 20(4):1057–66. doi:10.1093/humrep/deh740 121. Reister F, Frank HG, Heyl W, Kosanke G, Huppertz B, Schröder W, et al. 102. Svensson J, Jenmalm MC, Matussek A, Geffers R, Berg G, Ernerudh J. The distribution of macrophages in spiral arteries of the placental bed in Macrophages at the fetal-maternal interface express markers of alterna- pre-eclampsia differs from that in healthy patients. Placenta (1999) 20(2– tive activation and are induced by M-CSF and IL-10. J Immunol (2011) 3):229–33. doi:10.1053/plac.1998.0373 187(7):3671–82. doi:10.4049/jimmunol.1100130 122. Haeger M, Unander M, Norder-Hansson B, Tylman M, Bengtsson A. Comple- 103. Daiter E, Pampfer S, Yeung YG, Barad D, Stanley ER, Pollard JW. Expression of ment, neutrophil, and macrophage activation in women with severe preeclamp- colony-stimulating factor-1 in the human uterus and placenta. J Clin Endocrinol sia and the syndrome of hemolysis, elevated liver enzymes, and low platelet Metab (1992) 74(4):850–8. doi:10.1210/jc.74.4.850 count. Obstet Gynecol (1992) 79(1):19–26. Frontiers in Immunology | Inflammation June 2014 | Volume 5 | Article 298 | 10 Faas et al. Monocytes and macrophages in pregnancy and pre-eclampsia 123. Staff AC, Johnsen GM, Dechend R, Redman CW. Preeclampsia and uteropla- 129. Spaans F, Melgert BN, Chiang C, Borghuis T, Klok PA, De Vos P, et al. Extra- cental acute atherosis: immune and inflammatory factors. J Reprod Immunol cellular ATP decreases trophoblast invasion, spiral artery remodeling and (2014) 101-102:120–6. doi:10.1016/j.jri.2013.09.001 immune cells in the mesometrial triangle in pregnant rats. Placenta (2014). 124. Staff AC, Dechend R, Redman CW. Review: preeclampsia, acute atherosis of the doi:10.1016/j.placenta.2014.05.013 spiral arteries and future cardiovascular disease: two new hypotheses. Placenta (2013) 34(Suppl):S73–8. doi:10.1016/j.placenta.2012.11.022 Conflict of Interest Statement: The authors declare that the research was conducted 125. Prins JR, Faas MM, Melgert BN, Huitema S, Timmer A, Hylkema MN, in the absence of any commercial or financial relationships that could be construed et al. Altered expression of immune-associated genes in first-trimester as a potential conflict of interest. human decidua of pregnancies later complicated with hypertension or foetal growth restriction. Placenta (2012) 33(5):453–5. doi:10.1016/j.placenta.2012. Received: 01 May 2014; paper pending published: 26 May 2014; accepted: 12 June 2014; 02.010 published online: 30 June 2014. 126. Helige C, Ahammer H, Hammer A, Huppertz B, Frank HG, Dohr G. Tro- Citation: Faas MM, Spaans F and De Vos P (2014) Monocytes and macrophages in phoblastic invasion in vitro and in vivo: similarities and differences. Hum pregnancy and pre-eclampsia. Front. Immunol. 5:298. doi: 10.3389/fimmu.2014.00298 Reprod (2008) 23(10):2282–91. doi:10.1093/humrep/den198 This article was submitted to Inflammation, a section of the journal Frontiers in 127. Renaud SJ, Postovit LM, Macdonald-Goodfellow SK, McDonald GT, Caldwell Immunology. JD, Graham CH. Activated macrophages inhibit human cytotrophoblast inva- Copyright © 2014 Faas , Spaans and De Vos. This is an open-access article distributed siveness in vitro. Biol Reprod (2005) 73(2):237–43. doi:10.1095/biolreprod.104. under the terms of the Creative Commons Attribution License (CC BY). The use, dis- 038000 tribution or reproduction in other forums is permitted, provided the original author(s) 128. Renaud SJ, Macdonald-Goodfellow SK, Graham CH. Coordinated regulation or licensor are credited and that the original publication in this journal is cited, in of human trophoblast invasiveness by macrophages and interleukin 10. Biol accordance with accepted academic practice. No use, distribution or reproduction is Reprod (2007) 76(3):448–54. doi:10.1095/biolreprod.106.055376 permitted which does not comply with these terms. www.frontiersin.org June 2014 | Volume 5 | Article 298 | 11

Journal

Frontiers in ImmunologyPubmed Central

Published: Jun 30, 2014

There are no references for this article.