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Revisiting Mouse Peritoneal Macrophages: Heterogeneity, Development, and Function

Revisiting Mouse Peritoneal Macrophages: Heterogeneity, Development, and Function REVIEW published: 19 May 2015 doi: 10.3389/fimmu.2015.00225 Revisiting mouse peritoneal macrophages: heterogeneity, development, and function 1 1 Alexandra dos Anjos Cassado , Maria Regina D’Império Lima and 2,3 Karina Ramalho Bortoluci 1 2 Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil, Centro de Terapia Celular e Molecular (CTC-Mol), Universidade Federal de São Paulo, São Paulo, Brazil, Departamento de Ciências Biológicas, Campus Diadema, Universidade Federal de São Paulo, São Paulo, Brazil Tissue macrophages play a crucial role in the maintenance of tissue homeostasis and also contribute to inflammatory and reparatory responses during pathogenic infection and tissue injury. The high heterogeneity of these macrophages is consistent with their adaptation to distinct tissue environments and specialization to develop niche-specific functions. Although peritoneal macrophages are one of the best-studied macrophage Edited by: populations, recently it was demonstrated the co-existence of two subsets in mouse Florent Ginhoux, peritoneal cavity (PerC), which exhibit distinct phenotypes, functions, and origins. These Singapore Immunology Network, Singapore macrophage subsets have been classified, according to their morphology, as large peri- Reviewed by: toneal macrophages (LPMs) and small peritoneal macrophages (SPMs). LPMs, the most Xinjian Chen, abundant subset under steady state conditions, express high levels of F4/80 and low University of Utah, USA levels of class II molecules of the major histocompatibility complex (MHC). LPMs appear Thomas Marichal, University of Liège, Belgium tobeoriginatedfromembryogenicprecursors,andtheirmaintenanceinPerCisregulated *Correspondence: by expression of specific transcription factors and tissue-derived signals. Conversely, Alexandra dos Anjos Cassado, low high SPMs, a minor subset in unstimulated PerC, have a F4/80 MHC-II phenotype and Departamento de Imunologia, Instituto de Ciências Biomédicas, aregeneratedfrombone-marrow-derivedmyeloidprecursors.Inresponsetoinfectiousor Universidade de São Paulo, Av. inflammatorystimuli,thecellularcompositionofPerCisdramaticallyaltered,whereLPMs Professor Lineu Prestes, 1730, disappear and SPMs become the prevalent population together with their precursor, the Cidade Universitária, São Paulo, SP 05508-900, Brazil inflammatory monocyte. SPMs appear to be the major source of inflammatory mediators alecassado@hotmail.com in PerC during infection, whereas LPMs contribute for gut-associated lymphoid tissue- independent and retinoic acid-dependent IgA production by peritoneal B-1 cells. In the Specialty section: This article was submitted to Antigen previous years, considerable efforts have been made to broaden our understanding Presenting Cell Biology, a section of of LPM and SPM origin, transcriptional regulation, and functional profile. This review the journal Frontiers in Immunology addresses these issues, focusing on the impact of tissue-derived signals and external Received: 27 February 2015 Accepted: 26 April 2015 stimulation in the complex dynamics of peritoneal macrophage populations. Published: 19 May 2015 Keywords: peritoneal macrophages, peritoneal cavity, LPM, SPM, origin Citation: Cassado AA, D’Império Lima MR and Bortoluci KR (2015) Revisiting mouse Introduction peritoneal macrophages: heterogeneity, development, and Macrophages are resident cells found in almost all tissues of the body, where they assume specific function. phenotypesanddevelopdistinctfunctions.Tissuemacrophagesareconsideredasimmunesentinels Front. Immunol. 6:225. doi: 10.3389/fimmu.2015.00225 because of their strategic localization and their ability to initiate and modulate immune responses Frontiers in Immunology | www.frontiersin.org 1 May 2015 | Volume 6 | Article 225 Cassado et al. Peritoneal macrophage heterogeneity during pathogenic infection or tissue injury and to contribute Identification of Peritoneal Macrophages to the maintenance of tissue homeostasis (1–3). Macrophages Cohn and collaborators introduced the study of peritoneal were first identified in the late 19th century by Élie Metchnikoff macrophages (45–48). Indeed, a representative portion of the (1845–1916) and designated as large phagocytes (4, 5). Based current knowledge regarding macrophage biology, such as their on their phagocytic activity, macrophages were first classified as function,specialization,anddevelopmentstemsfromstudiesper- cells from the reticuloendothelial system, which also comprised formed using peritoneal macrophages as a cellular source. How- endothelial cells, fibroblasts, spleen and lymphoid reticular cells, ever,theexistenceoftworesidentmacrophagesubsetspresentin Kupffer cells, splenocytes, and monocytes (6). However, because the PerC was described recently (31). These macrophage subsets endocytosis performed by endothelial cells is a process that is were designated LPM and SPM according to their size. LPMs distinct from phagocytosis, by the late 1960s a new classification and SPMs were initially identified based on their differential system for mononuclear phagocytic cells as cells from “mononu- expressionofF4/80andCD11b,whereLPMsexpresshighlevelsof clear phagocytic system” (MPS) was proposed (7). The MPS was low low F4/80andCD11bwhileSPMsshowF4/80 CD11b phenotype defined as a group of phagocytic cells sharing morphological (Table 1). CD11b is an integrin that, together with CD18, forms andfunctionalsimilarities,includingpro-monocytes,monocytes, theCR3heterodimer(13,30,49),butisnotexclusivelyexpressed macrophages,dendriticcells(DCs),andtheirbonemarrow(BM) onmacrophagesandisfoundonseveralotherscelltypes,includ- progenitors (7–12). Although the phagocytic cells play similar ingpolymorphonuclearcells(50,51),DCs(52),andatlowlevels roles in orchestrating the immune response and maintaining tis- onBlymphocytes(53,54).F4/80,a160kDglycoproteinfromthe sue homeostasis (11), they represent cell populations that are epidermal growth factor (EGF)-transmembrane 7 (TM7) family, extremely heterogeneous (13), and the general classification of isexpressedbymacrophagesinseveralorgans,suchasthekidney mononuclear cells in a unique system is currently under intense (55), BM (56), epithelium (57), lung (58, 59), lymphoid organs discussion (12, 14). In this context, Guilliams et al. suggested a (60), and among others (61, 62), and it is not found on fibrob- classificationofMPScellsbasedprimarilyontheirontogenyand lasts, polymorphonuclear cells, and lymphocytes (63). However, secondaryontheirlocation,function,andphenotype,promoting peritoneal eosinophils show low levels of F4/80 (31) and some a better classification under both steady state and inflammatory macrophage subpopulations exhibit low levels or do not express conditions(14). F4/80,suchaswhitepulpandmarginalzonesplenicmacrophages In the last few years, a complex scenario to describe (30). Therefore, F4/80 expression levels distinguish macrophage macrophage origins has been developed (15–19), replacing the subpopulations,includingthoseresidinginthesametissue,such simplistic view of myeloid precursors giving rise to blood assubsetsfoundinthespleenandPerC(30,31,35).Inthissense, monocytes that, in turn, originate tissue macrophages (20– + + the great majority (approximately 90%) of F4/80 CD11b cells 22). For example, resident macrophages from brain, lung, liver, presentinthePerCfromseveralmousestrains,includingBALB/c, peritoneum, and spleen are not differentiated from mono- C57BL/6,129/S6,FVB/N,SJL/J,andRAG ,expresshighlevels cytes; instead, they are derived from an embryonic precursor ofthesemoleculesandcorrespondtotheLPMsubset,whereasthe and maintained by self-renewal (23–27). In addition to res- minorSPMsubsetexpresseslowlevelsofthesemarkers(31). ident macrophages, infiltrating monocytes are also found in An accurate evaluation of SPMs and LPMs by flow cytom- injured tissues, where they can differentiate into inflamma- etry and optical microscopy revealed that in addition to the tory macrophages or TNF-α- and inducible nitric oxide syn- differential expression of CD11b and F4/80, SPMs and LPMs thase (iNOS)-producing(Tip)-DCs (28). Currently, it is accepted display unique morphologies and phenotypes. LPMs assume the thatinflammatorymacrophagesandtissue-residentmacrophages comprise developmentally and functionally distinct populations (3,14,17,18,29). TABLE 1 | Phenotypic profile of SPMs and LPMs. Under steady state conditions, some tissues and serous cav- ities, including lung, spleen, and the peritoneal cavity (PerC), Surface molecule LPMs SPMs present distinct resident macrophage subpopulations. In the F4/80 +++ + spleen, at least three macrophage subsets are found: red pulp, CD11b +++ + metalophilic, and marginal zone macrophages (30). In the PerC, CD11c + two peritoneal macrophage subsets have been described: large MHC-II + ++ peritoneal macrophage (LPM) and small peritoneal macrophage GR1 + (SPM) (31). Mouse peritoneal macrophages are among the Ly6C best-studied macrophage populations in terms of cell biology, c-kit development, and inflammatory responses (24, 31–42). Peri- CD62L ++ Dectin-1 + ++ toneal macrophages play key roles in the control of infec- DC-Sign ++ tions and inflammatory pathologies (43, 44), as well as in the TLR4 ++ + maintenance of immune response robustness (40). Therefore, CD80 ++ + this review will discuss recent advances in our understanding CD86 +++ + of peritoneal macrophage subsets characterization, origin and CD40 ++ + functions, and the accurate experimental approaches to ana- 12/15-LOX + lyzethem. TIM4 + Frontiers in Immunology | www.frontiersin.org 2 May 2015 | Volume 6 | Article 225 Cassado et al. Peritoneal macrophage heterogeneity classicalmorphologydescribedformacrophagesafteradherence, GMP, termed the macrophage-DC precursor (MDP), expresses exhibiting prominent vacuolization and abundant cytoplasm, highlevelsofthefractalkinereceptorCX3CR1,c-kit,andCD115, whereas SPMs display a polarized morphology in culture, pre- and gives rise to circulating blood monocytes, some macrophage senting dendrites similar to DCs (35). Moreover, the analysis of populations and a common DC precursor (CDP), but does not acomplexpanelofcellsurfacemolecules(Table1)demonstrated originate granulocytes (15, 65, 66). The recruitment of mono- that SPMs express higher levels of MHC-II (IA ), dectin-1, and cytesubsetsundersteadystateorinflammatoryandpathological DC-sign endocytic receptors than LPMs. Moreover, half of SPM conditionsdependsonparticularchemokinesandtheexpression subset expresses high levels CD62L (31, 35, 36). Conversely, of their counterpart’s receptors. The Ly6C monocyte subset LPMs express higher levels of toll like receptor (TLR)-4 and migratesviaaCCR2-dependentpathway,whereasLy6C appears co-stimulatorymoleculesincomparisontoSPMs(31,35,36). to migrate in response to CX3CR1 signaling (67). Under steady Given that PerC is a singular compartment where special- state conditions, extravasated monocytes do not contribute to ized immune cells reside and interact, including macrophages, the pool of resident macrophages in many tissues (3, 15, 16). B cells, DCs, eosinophils, mast cells, neutrophils, T cells, nat- Ininflammatorysettings,theLy6C monocytesubsetdifferenti- ural killer (NK), and invariant NKT cells (31, 32, 35, 36, 64), atesintoinflammatorymacrophagesandmonocyte-derivedDCs, the identification of myeloid cells from PerC based on cell sur- suchasTip-DCs(15,16). face molecules is still a complex matter, particularly in terms Recent accumulating evidence supports the prenatal origin of of distinguishing macrophage subsets from DCs and inflamma- tissue-residentmacrophagesandtheideathattheyaremaintained tory monocytes. The expression of 12/15-lipoxygenase (LOX), locally by self-renewal throughout adult life, both in the steady Tim4,andLy6Bhasalsobeenexaminedtodiscriminateheteroge- stateandaftercellturnover,whichispredominantlyindependent neous macrophage subsets in PerC under steady state conditions ofhematopoiesis(17,18,23–27,29,68,69).Microglia,Langerhans and during peritonitis (24, 37, 38, 42). The high expression of cells,Kupffercells,redpulpsplenicmacrophages,lung,andperi- 12/15-LOX and Tim4 was observed in peritoneal macrophages, toneal macrophages are originated from embryogenic precursor which also express high levels of F4/80 and CD11b, correlating and proliferative cells maintained by self-renewal (23–27, 69– with the phenotype and frequencies observed for LPMs (24, 31, 71).Fetal-livermonocytesorprimitivemacrophagesfoundinthe 37, 38, 42). Conversely, 12/15-LOX cells and SPM share the yolk sac, an extraembryonic tissue, have been related with the + low high same CD11b F4/80 MHCII phenotype; however, 12/15- originoftissue-residentmacrophages.Inthiscontext,recentdate LOX cells express high levels of CD11c and co-stimulatory using yolk sac macrophages depletion and fate-mapping models molecules,suggestingthat12/15-LOX cellsandSPMsare,atleast demonstrated that yolk sac macrophages, which are generated inpart,distinctpopulations(31,35,37).Despitesimilaritiesincell from early erythro-myeloid progenitors (EMPs), are important morphologyandMHC-IIexpressionpresentedbySPMsandDCs, for development of macrophages in mid-gestation; however in thepossibilitythatSPMsmaybepartoftheperitonealDCpoolis adulthood, only microglia is maintained by these embryogenic excluded by the smaller size, the distinct and lack of the CD11b precursor(69).Incontrast,fetalmonocytesthatarederivedfrom and F4/80 expression presented by DCs and, primarily, by the late EMPs give rise to tissue-resident macrophages from liver, lower expression of CD11c (HL3 or N418 clones of monoclonal lung, skin, kidney and spleen (69). The exception to the origin anti-CD11c)onSPMscomparedwithLPMsortypicalperitoneal of resident macrophages is intestinal macrophages, which are DCs(31,35). continuouslyrepopulatedbycirculatingmonocytes(72). Given the cell complexity present in PerC and the impor- Understanding the dynamics of maintenance and recruitment tance of the development of efficient strategies to correctly ofperitonealmacrophagesisofparticularinterestsincethesecells identify macrophage subsets as well as to avoid contamination are involved in physiological as well as pathological processes, by other cell populations and misinterpretation of peritoneal such as peritonitis, tumors, and pancreatitis (40, 43, 44). Early macrophage studies, our group has proposed a simple way to studies demonstrated that peritoneal macrophages are main- identify peritoneal macrophage subsets using a four-color flow tained in PerC through self-renewal in the steady state or under high high cytometrystainingpanel.Fromdoublet,CD19 andCD11c inflammatoryconditions(73–76).Theomentum,afattissuethat discarded selected cell populations; the analysis of F4/80 cells connects the abdominal organs, is also involved in peritoneal basedonMHCIIexpressiondefinesthreedistinctsubpopulations, macrophage development through the proliferative capacities of high b-neg low b-high low b-neg F4/80 IA ,F4/80 IA ,andF4/80 IA ,whichcor- omental macrophages (75, 76). The combination of these early respond,respectively,toLPMs,SPMs,andgranulocytes(35). observations, which were acquired recently, with the technical advances to correctly identify the peritoneal macrophage subsets haspermittedtheontogenyoftheperitonealmacrophagesubsets Origin and Development of LPM and SPM tobeelucidated(24,31,36,39,40,42). The theories that explain the origin of macrophages have been Under steady state conditions, LPMs appear to be main- completely reformulated in the last few years. The differentia- tainedbyself-renewalandindependentofhematopoiesis(26,36), tion process of monocytes, macrophages, and DCs that occurs whereasSPMsareoriginatedfromcirculatingmonocytes(31,36, in the BM starts with the earliest progenitor, the hematopoietic 40) (Figure 1). Dates from Schulz et al. suggest that, in general, stem cell (HSC), and follows the common myeloid progenitor F4/80 expression by tissue macrophages correlated with yolk sac high low (CMP) and the granulocyte and macrophage progenitor (GMP) (F4/80 )andnothematopoietic(F4/80 )progenitors(25).In GFP/WT (16). The clonotypic BM-resident precursor differentiated from the CX3CR1 mice, Cain et al. (36) showed the presence of Frontiers in Immunology | www.frontiersin.org 3 May 2015 | Volume 6 | Article 225 Cassado et al. Peritoneal macrophage heterogeneity long-lived population, i.e., maintained at low levels of prolifera- tion(36).Conversely,thedetectionoflownumbersofproliferat- ingSPMsat6–10daysafteronepulseofBrdUsuggeststhatthese cells have a low proliferation rate under steady state conditions andareshort-livedcells(36). Studies with mice deficient in CCAAT/enhancer binding protein (C/EBP)b also support the notion that LPMs and SPMs represent distinct ontogenies, because in the absence of this transcription factor, PerC did not contain LPMs and exhibited increased numbers of SPMs (36). Interestingly, adop- tively transferred SPMs differentiated into LPMs in Cebpb mice. However, in control mice that have normal numbers of LPMs, only a small frequency of transferred SPMs acquired the hi low + F4/80 MHCII CD93 phenotype of LPMs. Based on these results,theauthorsproposedthatunderphysiologicalconditions, SPMsappeartocontributeinonlyasmallwaytogenerateLPMs, but SPMs could be involved in the maintenance of LPMs in sit- uations where this pool has been greatly reduced, such as under inflammatory conditions or following radiation ablation (36). These data are consistent with the findings of Yona et al. (26), FIGURE 1 | Distinct origin of peritoneal macrophage subsets. SPMs are whichdemonstratedthepresenceofmonocyte-derivedcellsinthe generated from hematopoietic stem cells (HSC) in the bone marrow (BM) by differentiation of inflammatory blood monocytes (31, 40). However, LPMs LPM compartment 8weeks after the i.p. injection of thioglycol- appear to be originated from progenitors from yolk sac and independent of late. Together with LPMs, a subset of proliferating BM-derived hematopoietic progenitors (69). Local proliferation of LPMs ensures inflammatory macrophage has also been associated with self- homeostatic maintenance by self-renewal (36). renewalmechanismsduringtheresolutionofperitonitisinduced by zymosan and thioglycollate (42). Conversely, LPMs do not seem to contribute to the SPM pool, even during inflammation. GFP cellsinDCandSPMpool,butnotintheLPMpopulation. Our group demonstrated that adoptively transferred CFDA-SE- Conversely, in the CX CR1CreRosa26R-FGFP mice, which show theactiveandpastexpressionofCX3CR1,thepresenceofGFP labeledLPMs1hafterLPSstimulationretaineditsphenotype,and cells was found within DC, SPM, and LPM populations. These no CFDA-SE cells were found in the SPM compartment until dataindicatethatSPMsareshort-livedcells,whereasLPMshavea 2daysafterstimulation(31). moredistantontogenicrelationshipwithaCX3CR1 progenitor, In the last year, a great advance in the understanding of the corroborating the idea that they originate from the yolk sac (36). transcriptionalcontrolofperitonealmacrophagesprovidednovel However,inchimericC57BL/6micereconstitutedwithC57BL/6- insights into this scenario (39, 40). The zinc finger transcrip- CD45.1 BM, around 80% of SPMs and more than 70% of LPMs tionfactorGATA-bindingprotein6(GATA6)appearstoregulate are CD45.1-expressing cells, demonstrating that both peritoneal the majority of peritoneal macrophage-specific genes (PMSGs). macrophage subsets differentiate from BM precursors after abla- Of note, GATA6 is selectively expressed by LPMs (40). Accord- tionofperitonealmacrophagesinducedbyirradiation(36).Data ingly, the number of LPMs were greatly reduced in peritoneal + mye from our group suggest that PerC recruited Ly6C monocytes lavages from GATA6-KO and Mac-GATA6 KO mice, which could give rise to SPMs during inflammatory conditions (31). have a GATA6 deficiency in all myeloid cells or only in the Confirming that SPMs are generated via the differentiation of macrophage lineages, respectively (39, 40). Interestingly, retinoic inflammatory monocytes recruited to PerC, reduced numbers of acid(RA)istheextracellularfactorthatregulatesGATA-6-specific SPMsarefoundinthePerCofCCR2 mice(40). gene expression in LPMs, because vitamin A depleted (VAD; The analysis of Ki67 and phosphorylated histone H3 (pHH3 the RA precursor) mice exhibited a decrease in GATA6 expres- at a discrete stage of mitosis) staining and the quantification of sion and LPM numbers (40). Moreover, the stimulation of peri- cell cycle and basal DNA content revealed that the number of toneal macrophages from VAD mice with all-trans RA restored high high proliferating F4/80 CD11b cells decreases in 12-week-old the expression of GATA-6 and many PMSGs at levels found in mice compared with proliferation capacity of this population in peritoneal macrophages from control mice. In addition to the newborn mice (15days to 4weeks) (24). After 12–16weeks, the regulationofgeneexpressionprofilinginperitonealmacrophages, high high number of F4/80 CD11b cells in PerC is maintained under GATA-6appearstobeinvolvedinthecontroloftheproliferation, a low rate of proliferation, which suggests that the number of survival,andmetabolismofthesecells(39,77).GATA-6-deficient high high F4/80 CD11b peritonealcellsincreasesduringmousedevel- macrophages demonstrate an altered proliferation state during (flox/flox) opment until PerC acquires sufficient homeostatic cell numbers peritonitis (39). Moreover, Lyz2-CreGATA6 mice also 24). Indeed, BrdU-labeled LPM frequencies after a single BrdU ( exhibitreducednumbersofperitonealmacrophages,whichcould pulse were 7 and 15-fold lower than those found in HSC and beexplainedbytheperturbationintheirmetabolism,culminating GMP, respectively. Moreover, the presence of BrdU LPMs was in the high frequency of cell death found in this compartment detectable 14days after BrdU pulse, suggesting that they are a (77). Despite great contributions to our understanding in the Frontiers in Immunology | www.frontiersin.org 4 May 2015 | Volume 6 | Article 225 Cassado et al. Peritoneal macrophage heterogeneity involvement of GATA-6 in peritoneal macrophage development, LPMs, SPMs, B-1 cells, conventional B-2 cells, T cells, NK cells, metabolism, self-maintenance, and survival, the existence of dis- DCs,andgranulocytes(mostlyeosinophils)(31,35).B1cellscon- tinctpathwaysthatcouldgovernthetranscriptionalregulationof stitutethemajorityofthePerCcellpopulation,whereastheSPM SPMsremainslargelyunknown. and LPM frequencies represent 30–35% of total peritoneal cells In addition to transcriptional regulation, signaling factors (31, 35) (Figure 2A). However, after inflammatory or infectious derived from the microenvironment also play an essential role stimuli, there is a dramatic alteration in cell numbers and the in promoting the development and phenotype of tissue-resident frequenciesofeachofPerCcellsubpopulation.Withregardtothe macrophages. For example, TGF-β1 signaling is required for myeloid compartment, modifications in PerC cell composition the development of the microglia population and to regulate a include the disappearance of LPMs, increases in SPM frequency microglia expression program through the Smad tissue factors andnumbers,andamassiverecruitmentofinflammatorymono- (78–80). Heme has been shown to induce Spi-c, a transcription cytes(24,31,35,36,40)(Figure2B). factor important for red pulp macrophage development (81, 82). The“macrophagedisappearancereaction”(MDR)inPerChas Finally, in PerC, omentum-derived RA promotes the expression been extensively described during delayed-type hypersensitivity of GATA-6 in the LPM subset, determining its localization and (DTH) and acute inflammatory processes (84). MDR has been functions (40), even if the factors that maintain the SPM pool associated with cell death, emigration to draining lymph nodes, understeadystateconditionsstillremaintobeelucidated. or adherence of macrophages to structural tissues. LPMs are the uniqueperitonealmacrophagesubsetthatdisappearsfromPerC, Dynamics and Function of Peritoneal which is attributed not to cell death but rather to their migration to the omentum (31, 40). LPM disappearance in response to Macrophage Subsets inflammatory stimuli is accompanied by an increase in SPM and Mouse PerC is a compartment where many cell types co-habitat inflammatorymonocytenumbers(24,31,35,36,40)(Figure2B), and interact, similar to the secondary lymphoid organs. In addi- and has been correlated with the renewal and improvement of tion, PerC is a unique body compartment that contains B-1 cells immune conditions of the PerC (35). Adherent peritoneal cells (83). Under steady state conditions, the peritoneal cells comprise from naive mice, which are composed primarily of LPM, exhibit FIGURE 2 | Summary of the dynamic of peritoneal macrophage from zymosan and T. cruzi stimulated mice contribute to effector function of PerC through secretion of high levels of NO and presence of IL-12-producing subsets. (A) Under homeostatic conditions, peritoneal macrophages comprise two subsets LPMs and SPMs (31). LPMs, which are the major cells (35). In response to LPS in vivo, SPMs produce several inflammatory cytokines, such as IL-12, MIP-1α, TNF-α, and RANTES, whereas LPMs peritoneal macrophage population, appear to be responsible for phagocytosis of apoptotic cell and tissue repair (36). (B) At the outset of inflammation, the produce enhanced amounts of G-CSF, GM-CSF, and KC (36). LPMs, which myeloid compartment is modified in general by disappearance of LPMs, migrate to omentum by a retinoic acid and GATA-6-dependent way in increase of SPMs numbers, and monocytes influx (31, 35, 36, 40). The response to in vivo LPS stimulation or vitamin-A deprivation, return to PerC changes in the myeloid cells from zymosan, T. cruzi, and LPS stimulated or and appear to be correlated with GALT-independent and TGF-β2-dependent thioglicollate-elicited PerC result in the gain of immune state (35, 36). SPMs IgA production by B-1 cells in the intestine (40). Frontiers in Immunology | www.frontiersin.org 5 May 2015 | Volume 6 | Article 225 Cassado et al. Peritoneal macrophage heterogeneity a high frequency of cells stained for β-galactosamine (β-gal), a assays, SPMs appear to develop an efficient profile to control infectionsasM1macrophages,whereasLPMsassumearoleinthe senescence marker (85–87). These cells are unable to secrete NO in response to LPS challenge (35). In contrast, adherent peri- maintenanceofPerCphysiologicalconditionsasM2oralternative macrophages. Despite the preserved phagocytic ability of LPMs, tonealcellsfromTrypanosomacruziorzymosan-stimulatedmice in which the main cell population constitutes SPMs and mono- higher numbers of zymosan and E. coli were found inside of low int + SPMsatearlytimepointsafteri.p.injection(31,35).Conversely, cytes (F4/80 MHCII Ly-6C ), respectively, display a signifi- cantreductioninthefrequencyofβ-gal-positivecellsandsecrete at 1h after challenge, LPMs appear to present a higher phago- high levels of NO in response to LPS (35). The frequency of IL- cytic index of apoptotic thymocytes in comparison to SPMs (36) 12-producing cells after in vitro LPS plus IFN-γ stimulation was (Figure2A). also higher within myelo-monocytic cells from mice exposed to In addition, it was recently demonstrated that LPMs have a unique ability to induce gut-associated lymphoid tissue zymosan and T. cruzi than the frequencies of IL-12-producing cells found in unstimulated mice (35). In response to Staphylo- (GALT)-independent IgA production by peritoneal B-1 cells (40) (Figure 2B). RA and TGF-β2 are the most critical factors coccusepidermidiscell-free(SES)supernatantinvivostimulation, low + F4/80 CD11b cells (consisting of SPMs and DCs) produced to induce IgA class switching, and the production of TGF-β2 is regulated by the Tgfb2 and Ltbp1 genes, which are expressed by enhancedlevelsofIL-1β,IL-1α,TNF-α,andIL-12inthepresence or absence of subsequent SES treatment (37). In contrast, the LPMsinaGATA-6-dependentmanner.Thisprocessisregulated by the abundant presence of RA in the omentum, which is supernatants of adherent cells from naïve mice treated with SES were found to contain high levels of MCP-1, MCP-1α, MIP- responsible for the induction of GATA-6 expression in LPMs that migrates to this tissue. The dynamic of LPM migration 1β, and G-CSF (37). It is important to note that 4days after thioglycollateinjection,peritonealcells,anextensivelystudiedcell betweenthePerCandtheomentumafterthestimulationofPerC population (88–91), also consist primarily of SPMs and inflam- is correlated with their disappearance and the return to basal numbers of LPMs later after stimulation with LPS, zymosan, matory monocytes (31, 40). The increase in SPM numbers and theinfluxofinflammatorymonocytesthatwillgiverisetoSPMs and thioglycollate (24, 31, 35, 36, 39, 40). This observation suggeststhatLPMscanreturntoPerCtoresolveaninfectiousor greatly contribute to the improvement of the capacity of PerC to deal with inflammatory stimuli. Indeed, although neither SPMs inflammatoryprocess.Therefore,thepresenceoftwospecialized macrophage subsets in PerC is crucial to maintain the health of norLPMsproducesignificantlevelsofpro-oranti-inflammatory cytokines under steady state conditions (35–37), SPMs appear to thiscompartmentunderdifferentsituations. developapro-inflammatoryprofileinresponsetoinvitrostimuli. SPMs produced high levels of TNF-α, MIP-1α, and RANTES in Concluding Remarks response to LPS, whereas LPMs were the unique population that producedabundantlevelsofG-CSF,GM-CSF,andKCinresponse Peritoneal macrophages represent one of the most studied tothesamestimulus(36)(Figure2B). macrophage populations. However, the existence of two pheno- The NO secretion and pro-inflammatory cytokine produc- typicallyandfunctionallydistinctsubsets,LPMsandSPMs,resid- tion are the most important functions of activated macrophages inginthePerCwasrecognizedrecently(31).Inthelastyear,great advances in our understanding of the transcriptional regulation by inflammatory stimulation and assigns the M1 profile (13, 34, 92–97). The functional profile of peritoneal macrophages of peritoneal macrophages have brought novel insights into the identification of LPMs and SPMs (39, 40). GATA-6, an LPM- was previous studied by our group and others (33, 34). Peri- tonealmacrophagesfromTh1-pronemousestrains(C57BL/6and restricted transcription factor, regulates many PMSGs, including thoserelatedtothemaintenanceofLPMsinPerC(40)andthose B10.A)areeasilyactivatedtoproduceNOinresponsetorIFN-γor LPS,characterizingtheM1profile.Incontrast,macrophagesfrom that determine their function (40), metabolism, proliferation, and cell survival (39, 77). Under steady state conditions, LPMs Th2-prone mouse strains (BALB/c and DBA/2) exhibit a weak NO response as a consequence of high levels of spontaneously appeartooriginateindependentlyfromhematopoieticprecursors secreted TGF-β1 (34). Moreover, the cells from C57BL/6 IL- and retained the ability to proliferate in situ, maintaining phys- 12p40-deficient mice have a bias toward the M2 profile, indi- iological numbers (26, 36). Conversely, SPMs appear to origi- cating that IL-12 is required for M1 polarization of peritoneal nate from circulating monocytes (31, 36, 40), and their numbers increase remarkably under inflammatory conditions. Of note, macrophages(33).AlthoughLPMsfromnaïvemicecanproduce NO afterin vitroLPS stimulation,SPMsproduce higherlevelsof SPMs together with their precursor, the inflammatory mono- cyte population, are the major myeloid populations present in NOthanLPMsfollowinginvivoLPSstimulation.TheNOsecre- tion by LPMs was also detected by flow cytometry in Escherichia elicitedPerC,andareanexcellentresourcetostudythebiologyof inflammatory macrophages. SPMs and LPMs exhibit specialized coliinoculatedmice(31),whereasnitritewasnotproducedinvitro by LPS-stimulated adherent peritoneal cells from control mice, functions in the PerC, where SPMs present a pro-inflammatory functionalprofile,andLPMsappeartohavearoleinthemainte- which is composed mainly by LPMs (35). In addition, adherent cellsobtained48hafterT.cruziinfection,whicharemostlycom- nance of PerC physiological conditions. Moreover, the particular interactionsbetweenmacrophagesubsetsandotherperitonealcell posed by SPMs, were the unique source of NO without in vitro subsequent challenge with LPS (35). In resume, the SPM and populations appear to play crucial roles in PerC immune state. LPMsubsetscannotbeaccommodatedintheM1/M2framework Although the consequences of the crosstalk between SPMs and considering the NO secretion. However, considering phagocytic peritonealTandBlymphocytesremaintobeclarified,LPMsare Frontiers in Immunology | www.frontiersin.org 6 May 2015 | Volume 6 | Article 225 Cassado et al. Peritoneal macrophage heterogeneity requiredfor GALT-independent andRA-dependent IgA produc- Acknowledgments tion by peritoneal B-1 cells (40). 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Revisiting Mouse Peritoneal Macrophages: Heterogeneity, Development, and Function

Frontiers in Immunology , Volume 6 – May 19, 2015

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Abstract

REVIEW published: 19 May 2015 doi: 10.3389/fimmu.2015.00225 Revisiting mouse peritoneal macrophages: heterogeneity, development, and function 1 1 Alexandra dos Anjos Cassado , Maria Regina D’Império Lima and 2,3 Karina Ramalho Bortoluci 1 2 Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil, Centro de Terapia Celular e Molecular (CTC-Mol), Universidade Federal de São Paulo, São Paulo, Brazil, Departamento de Ciências Biológicas, Campus Diadema, Universidade Federal de São Paulo, São Paulo, Brazil Tissue macrophages play a crucial role in the maintenance of tissue homeostasis and also contribute to inflammatory and reparatory responses during pathogenic infection and tissue injury. The high heterogeneity of these macrophages is consistent with their adaptation to distinct tissue environments and specialization to develop niche-specific functions. Although peritoneal macrophages are one of the best-studied macrophage Edited by: populations, recently it was demonstrated the co-existence of two subsets in mouse Florent Ginhoux, peritoneal cavity (PerC), which exhibit distinct phenotypes, functions, and origins. These Singapore Immunology Network, Singapore macrophage subsets have been classified, according to their morphology, as large peri- Reviewed by: toneal macrophages (LPMs) and small peritoneal macrophages (SPMs). LPMs, the most Xinjian Chen, abundant subset under steady state conditions, express high levels of F4/80 and low University of Utah, USA levels of class II molecules of the major histocompatibility complex (MHC). LPMs appear Thomas Marichal, University of Liège, Belgium tobeoriginatedfromembryogenicprecursors,andtheirmaintenanceinPerCisregulated *Correspondence: by expression of specific transcription factors and tissue-derived signals. Conversely, Alexandra dos Anjos Cassado, low high SPMs, a minor subset in unstimulated PerC, have a F4/80 MHC-II phenotype and Departamento de Imunologia, Instituto de Ciências Biomédicas, aregeneratedfrombone-marrow-derivedmyeloidprecursors.Inresponsetoinfectiousor Universidade de São Paulo, Av. inflammatorystimuli,thecellularcompositionofPerCisdramaticallyaltered,whereLPMs Professor Lineu Prestes, 1730, disappear and SPMs become the prevalent population together with their precursor, the Cidade Universitária, São Paulo, SP 05508-900, Brazil inflammatory monocyte. SPMs appear to be the major source of inflammatory mediators alecassado@hotmail.com in PerC during infection, whereas LPMs contribute for gut-associated lymphoid tissue- independent and retinoic acid-dependent IgA production by peritoneal B-1 cells. In the Specialty section: This article was submitted to Antigen previous years, considerable efforts have been made to broaden our understanding Presenting Cell Biology, a section of of LPM and SPM origin, transcriptional regulation, and functional profile. This review the journal Frontiers in Immunology addresses these issues, focusing on the impact of tissue-derived signals and external Received: 27 February 2015 Accepted: 26 April 2015 stimulation in the complex dynamics of peritoneal macrophage populations. Published: 19 May 2015 Keywords: peritoneal macrophages, peritoneal cavity, LPM, SPM, origin Citation: Cassado AA, D’Império Lima MR and Bortoluci KR (2015) Revisiting mouse Introduction peritoneal macrophages: heterogeneity, development, and Macrophages are resident cells found in almost all tissues of the body, where they assume specific function. phenotypesanddevelopdistinctfunctions.Tissuemacrophagesareconsideredasimmunesentinels Front. Immunol. 6:225. doi: 10.3389/fimmu.2015.00225 because of their strategic localization and their ability to initiate and modulate immune responses Frontiers in Immunology | www.frontiersin.org 1 May 2015 | Volume 6 | Article 225 Cassado et al. Peritoneal macrophage heterogeneity during pathogenic infection or tissue injury and to contribute Identification of Peritoneal Macrophages to the maintenance of tissue homeostasis (1–3). Macrophages Cohn and collaborators introduced the study of peritoneal were first identified in the late 19th century by Élie Metchnikoff macrophages (45–48). Indeed, a representative portion of the (1845–1916) and designated as large phagocytes (4, 5). Based current knowledge regarding macrophage biology, such as their on their phagocytic activity, macrophages were first classified as function,specialization,anddevelopmentstemsfromstudiesper- cells from the reticuloendothelial system, which also comprised formed using peritoneal macrophages as a cellular source. How- endothelial cells, fibroblasts, spleen and lymphoid reticular cells, ever,theexistenceoftworesidentmacrophagesubsetspresentin Kupffer cells, splenocytes, and monocytes (6). However, because the PerC was described recently (31). These macrophage subsets endocytosis performed by endothelial cells is a process that is were designated LPM and SPM according to their size. LPMs distinct from phagocytosis, by the late 1960s a new classification and SPMs were initially identified based on their differential system for mononuclear phagocytic cells as cells from “mononu- expressionofF4/80andCD11b,whereLPMsexpresshighlevelsof clear phagocytic system” (MPS) was proposed (7). The MPS was low low F4/80andCD11bwhileSPMsshowF4/80 CD11b phenotype defined as a group of phagocytic cells sharing morphological (Table 1). CD11b is an integrin that, together with CD18, forms andfunctionalsimilarities,includingpro-monocytes,monocytes, theCR3heterodimer(13,30,49),butisnotexclusivelyexpressed macrophages,dendriticcells(DCs),andtheirbonemarrow(BM) onmacrophagesandisfoundonseveralotherscelltypes,includ- progenitors (7–12). Although the phagocytic cells play similar ingpolymorphonuclearcells(50,51),DCs(52),andatlowlevels roles in orchestrating the immune response and maintaining tis- onBlymphocytes(53,54).F4/80,a160kDglycoproteinfromthe sue homeostasis (11), they represent cell populations that are epidermal growth factor (EGF)-transmembrane 7 (TM7) family, extremely heterogeneous (13), and the general classification of isexpressedbymacrophagesinseveralorgans,suchasthekidney mononuclear cells in a unique system is currently under intense (55), BM (56), epithelium (57), lung (58, 59), lymphoid organs discussion (12, 14). In this context, Guilliams et al. suggested a (60), and among others (61, 62), and it is not found on fibrob- classificationofMPScellsbasedprimarilyontheirontogenyand lasts, polymorphonuclear cells, and lymphocytes (63). However, secondaryontheirlocation,function,andphenotype,promoting peritoneal eosinophils show low levels of F4/80 (31) and some a better classification under both steady state and inflammatory macrophage subpopulations exhibit low levels or do not express conditions(14). F4/80,suchaswhitepulpandmarginalzonesplenicmacrophages In the last few years, a complex scenario to describe (30). Therefore, F4/80 expression levels distinguish macrophage macrophage origins has been developed (15–19), replacing the subpopulations,includingthoseresidinginthesametissue,such simplistic view of myeloid precursors giving rise to blood assubsetsfoundinthespleenandPerC(30,31,35).Inthissense, monocytes that, in turn, originate tissue macrophages (20– + + the great majority (approximately 90%) of F4/80 CD11b cells 22). For example, resident macrophages from brain, lung, liver, presentinthePerCfromseveralmousestrains,includingBALB/c, peritoneum, and spleen are not differentiated from mono- C57BL/6,129/S6,FVB/N,SJL/J,andRAG ,expresshighlevels cytes; instead, they are derived from an embryonic precursor ofthesemoleculesandcorrespondtotheLPMsubset,whereasthe and maintained by self-renewal (23–27). In addition to res- minorSPMsubsetexpresseslowlevelsofthesemarkers(31). ident macrophages, infiltrating monocytes are also found in An accurate evaluation of SPMs and LPMs by flow cytom- injured tissues, where they can differentiate into inflamma- etry and optical microscopy revealed that in addition to the tory macrophages or TNF-α- and inducible nitric oxide syn- differential expression of CD11b and F4/80, SPMs and LPMs thase (iNOS)-producing(Tip)-DCs (28). Currently, it is accepted display unique morphologies and phenotypes. LPMs assume the thatinflammatorymacrophagesandtissue-residentmacrophages comprise developmentally and functionally distinct populations (3,14,17,18,29). TABLE 1 | Phenotypic profile of SPMs and LPMs. Under steady state conditions, some tissues and serous cav- ities, including lung, spleen, and the peritoneal cavity (PerC), Surface molecule LPMs SPMs present distinct resident macrophage subpopulations. In the F4/80 +++ + spleen, at least three macrophage subsets are found: red pulp, CD11b +++ + metalophilic, and marginal zone macrophages (30). In the PerC, CD11c + two peritoneal macrophage subsets have been described: large MHC-II + ++ peritoneal macrophage (LPM) and small peritoneal macrophage GR1 + (SPM) (31). Mouse peritoneal macrophages are among the Ly6C best-studied macrophage populations in terms of cell biology, c-kit development, and inflammatory responses (24, 31–42). Peri- CD62L ++ Dectin-1 + ++ toneal macrophages play key roles in the control of infec- DC-Sign ++ tions and inflammatory pathologies (43, 44), as well as in the TLR4 ++ + maintenance of immune response robustness (40). Therefore, CD80 ++ + this review will discuss recent advances in our understanding CD86 +++ + of peritoneal macrophage subsets characterization, origin and CD40 ++ + functions, and the accurate experimental approaches to ana- 12/15-LOX + lyzethem. TIM4 + Frontiers in Immunology | www.frontiersin.org 2 May 2015 | Volume 6 | Article 225 Cassado et al. Peritoneal macrophage heterogeneity classicalmorphologydescribedformacrophagesafteradherence, GMP, termed the macrophage-DC precursor (MDP), expresses exhibiting prominent vacuolization and abundant cytoplasm, highlevelsofthefractalkinereceptorCX3CR1,c-kit,andCD115, whereas SPMs display a polarized morphology in culture, pre- and gives rise to circulating blood monocytes, some macrophage senting dendrites similar to DCs (35). Moreover, the analysis of populations and a common DC precursor (CDP), but does not acomplexpanelofcellsurfacemolecules(Table1)demonstrated originate granulocytes (15, 65, 66). The recruitment of mono- that SPMs express higher levels of MHC-II (IA ), dectin-1, and cytesubsetsundersteadystateorinflammatoryandpathological DC-sign endocytic receptors than LPMs. Moreover, half of SPM conditionsdependsonparticularchemokinesandtheexpression subset expresses high levels CD62L (31, 35, 36). Conversely, of their counterpart’s receptors. The Ly6C monocyte subset LPMs express higher levels of toll like receptor (TLR)-4 and migratesviaaCCR2-dependentpathway,whereasLy6C appears co-stimulatorymoleculesincomparisontoSPMs(31,35,36). to migrate in response to CX3CR1 signaling (67). Under steady Given that PerC is a singular compartment where special- state conditions, extravasated monocytes do not contribute to ized immune cells reside and interact, including macrophages, the pool of resident macrophages in many tissues (3, 15, 16). B cells, DCs, eosinophils, mast cells, neutrophils, T cells, nat- Ininflammatorysettings,theLy6C monocytesubsetdifferenti- ural killer (NK), and invariant NKT cells (31, 32, 35, 36, 64), atesintoinflammatorymacrophagesandmonocyte-derivedDCs, the identification of myeloid cells from PerC based on cell sur- suchasTip-DCs(15,16). face molecules is still a complex matter, particularly in terms Recent accumulating evidence supports the prenatal origin of of distinguishing macrophage subsets from DCs and inflamma- tissue-residentmacrophagesandtheideathattheyaremaintained tory monocytes. The expression of 12/15-lipoxygenase (LOX), locally by self-renewal throughout adult life, both in the steady Tim4,andLy6Bhasalsobeenexaminedtodiscriminateheteroge- stateandaftercellturnover,whichispredominantlyindependent neous macrophage subsets in PerC under steady state conditions ofhematopoiesis(17,18,23–27,29,68,69).Microglia,Langerhans and during peritonitis (24, 37, 38, 42). The high expression of cells,Kupffercells,redpulpsplenicmacrophages,lung,andperi- 12/15-LOX and Tim4 was observed in peritoneal macrophages, toneal macrophages are originated from embryogenic precursor which also express high levels of F4/80 and CD11b, correlating and proliferative cells maintained by self-renewal (23–27, 69– with the phenotype and frequencies observed for LPMs (24, 31, 71).Fetal-livermonocytesorprimitivemacrophagesfoundinthe 37, 38, 42). Conversely, 12/15-LOX cells and SPM share the yolk sac, an extraembryonic tissue, have been related with the + low high same CD11b F4/80 MHCII phenotype; however, 12/15- originoftissue-residentmacrophages.Inthiscontext,recentdate LOX cells express high levels of CD11c and co-stimulatory using yolk sac macrophages depletion and fate-mapping models molecules,suggestingthat12/15-LOX cellsandSPMsare,atleast demonstrated that yolk sac macrophages, which are generated inpart,distinctpopulations(31,35,37).Despitesimilaritiesincell from early erythro-myeloid progenitors (EMPs), are important morphologyandMHC-IIexpressionpresentedbySPMsandDCs, for development of macrophages in mid-gestation; however in thepossibilitythatSPMsmaybepartoftheperitonealDCpoolis adulthood, only microglia is maintained by these embryogenic excluded by the smaller size, the distinct and lack of the CD11b precursor(69).Incontrast,fetalmonocytesthatarederivedfrom and F4/80 expression presented by DCs and, primarily, by the late EMPs give rise to tissue-resident macrophages from liver, lower expression of CD11c (HL3 or N418 clones of monoclonal lung, skin, kidney and spleen (69). The exception to the origin anti-CD11c)onSPMscomparedwithLPMsortypicalperitoneal of resident macrophages is intestinal macrophages, which are DCs(31,35). continuouslyrepopulatedbycirculatingmonocytes(72). Given the cell complexity present in PerC and the impor- Understanding the dynamics of maintenance and recruitment tance of the development of efficient strategies to correctly ofperitonealmacrophagesisofparticularinterestsincethesecells identify macrophage subsets as well as to avoid contamination are involved in physiological as well as pathological processes, by other cell populations and misinterpretation of peritoneal such as peritonitis, tumors, and pancreatitis (40, 43, 44). Early macrophage studies, our group has proposed a simple way to studies demonstrated that peritoneal macrophages are main- identify peritoneal macrophage subsets using a four-color flow tained in PerC through self-renewal in the steady state or under high high cytometrystainingpanel.Fromdoublet,CD19 andCD11c inflammatoryconditions(73–76).Theomentum,afattissuethat discarded selected cell populations; the analysis of F4/80 cells connects the abdominal organs, is also involved in peritoneal basedonMHCIIexpressiondefinesthreedistinctsubpopulations, macrophage development through the proliferative capacities of high b-neg low b-high low b-neg F4/80 IA ,F4/80 IA ,andF4/80 IA ,whichcor- omental macrophages (75, 76). The combination of these early respond,respectively,toLPMs,SPMs,andgranulocytes(35). observations, which were acquired recently, with the technical advances to correctly identify the peritoneal macrophage subsets haspermittedtheontogenyoftheperitonealmacrophagesubsets Origin and Development of LPM and SPM tobeelucidated(24,31,36,39,40,42). The theories that explain the origin of macrophages have been Under steady state conditions, LPMs appear to be main- completely reformulated in the last few years. The differentia- tainedbyself-renewalandindependentofhematopoiesis(26,36), tion process of monocytes, macrophages, and DCs that occurs whereasSPMsareoriginatedfromcirculatingmonocytes(31,36, in the BM starts with the earliest progenitor, the hematopoietic 40) (Figure 1). Dates from Schulz et al. suggest that, in general, stem cell (HSC), and follows the common myeloid progenitor F4/80 expression by tissue macrophages correlated with yolk sac high low (CMP) and the granulocyte and macrophage progenitor (GMP) (F4/80 )andnothematopoietic(F4/80 )progenitors(25).In GFP/WT (16). The clonotypic BM-resident precursor differentiated from the CX3CR1 mice, Cain et al. (36) showed the presence of Frontiers in Immunology | www.frontiersin.org 3 May 2015 | Volume 6 | Article 225 Cassado et al. Peritoneal macrophage heterogeneity long-lived population, i.e., maintained at low levels of prolifera- tion(36).Conversely,thedetectionoflownumbersofproliferat- ingSPMsat6–10daysafteronepulseofBrdUsuggeststhatthese cells have a low proliferation rate under steady state conditions andareshort-livedcells(36). Studies with mice deficient in CCAAT/enhancer binding protein (C/EBP)b also support the notion that LPMs and SPMs represent distinct ontogenies, because in the absence of this transcription factor, PerC did not contain LPMs and exhibited increased numbers of SPMs (36). Interestingly, adop- tively transferred SPMs differentiated into LPMs in Cebpb mice. However, in control mice that have normal numbers of LPMs, only a small frequency of transferred SPMs acquired the hi low + F4/80 MHCII CD93 phenotype of LPMs. Based on these results,theauthorsproposedthatunderphysiologicalconditions, SPMsappeartocontributeinonlyasmallwaytogenerateLPMs, but SPMs could be involved in the maintenance of LPMs in sit- uations where this pool has been greatly reduced, such as under inflammatory conditions or following radiation ablation (36). These data are consistent with the findings of Yona et al. (26), FIGURE 1 | Distinct origin of peritoneal macrophage subsets. SPMs are whichdemonstratedthepresenceofmonocyte-derivedcellsinthe generated from hematopoietic stem cells (HSC) in the bone marrow (BM) by differentiation of inflammatory blood monocytes (31, 40). However, LPMs LPM compartment 8weeks after the i.p. injection of thioglycol- appear to be originated from progenitors from yolk sac and independent of late. Together with LPMs, a subset of proliferating BM-derived hematopoietic progenitors (69). Local proliferation of LPMs ensures inflammatory macrophage has also been associated with self- homeostatic maintenance by self-renewal (36). renewalmechanismsduringtheresolutionofperitonitisinduced by zymosan and thioglycollate (42). Conversely, LPMs do not seem to contribute to the SPM pool, even during inflammation. GFP cellsinDCandSPMpool,butnotintheLPMpopulation. Our group demonstrated that adoptively transferred CFDA-SE- Conversely, in the CX CR1CreRosa26R-FGFP mice, which show theactiveandpastexpressionofCX3CR1,thepresenceofGFP labeledLPMs1hafterLPSstimulationretaineditsphenotype,and cells was found within DC, SPM, and LPM populations. These no CFDA-SE cells were found in the SPM compartment until dataindicatethatSPMsareshort-livedcells,whereasLPMshavea 2daysafterstimulation(31). moredistantontogenicrelationshipwithaCX3CR1 progenitor, In the last year, a great advance in the understanding of the corroborating the idea that they originate from the yolk sac (36). transcriptionalcontrolofperitonealmacrophagesprovidednovel However,inchimericC57BL/6micereconstitutedwithC57BL/6- insights into this scenario (39, 40). The zinc finger transcrip- CD45.1 BM, around 80% of SPMs and more than 70% of LPMs tionfactorGATA-bindingprotein6(GATA6)appearstoregulate are CD45.1-expressing cells, demonstrating that both peritoneal the majority of peritoneal macrophage-specific genes (PMSGs). macrophage subsets differentiate from BM precursors after abla- Of note, GATA6 is selectively expressed by LPMs (40). Accord- tionofperitonealmacrophagesinducedbyirradiation(36).Data ingly, the number of LPMs were greatly reduced in peritoneal + mye from our group suggest that PerC recruited Ly6C monocytes lavages from GATA6-KO and Mac-GATA6 KO mice, which could give rise to SPMs during inflammatory conditions (31). have a GATA6 deficiency in all myeloid cells or only in the Confirming that SPMs are generated via the differentiation of macrophage lineages, respectively (39, 40). Interestingly, retinoic inflammatory monocytes recruited to PerC, reduced numbers of acid(RA)istheextracellularfactorthatregulatesGATA-6-specific SPMsarefoundinthePerCofCCR2 mice(40). gene expression in LPMs, because vitamin A depleted (VAD; The analysis of Ki67 and phosphorylated histone H3 (pHH3 the RA precursor) mice exhibited a decrease in GATA6 expres- at a discrete stage of mitosis) staining and the quantification of sion and LPM numbers (40). Moreover, the stimulation of peri- cell cycle and basal DNA content revealed that the number of toneal macrophages from VAD mice with all-trans RA restored high high proliferating F4/80 CD11b cells decreases in 12-week-old the expression of GATA-6 and many PMSGs at levels found in mice compared with proliferation capacity of this population in peritoneal macrophages from control mice. In addition to the newborn mice (15days to 4weeks) (24). After 12–16weeks, the regulationofgeneexpressionprofilinginperitonealmacrophages, high high number of F4/80 CD11b cells in PerC is maintained under GATA-6appearstobeinvolvedinthecontroloftheproliferation, a low rate of proliferation, which suggests that the number of survival,andmetabolismofthesecells(39,77).GATA-6-deficient high high F4/80 CD11b peritonealcellsincreasesduringmousedevel- macrophages demonstrate an altered proliferation state during (flox/flox) opment until PerC acquires sufficient homeostatic cell numbers peritonitis (39). Moreover, Lyz2-CreGATA6 mice also 24). Indeed, BrdU-labeled LPM frequencies after a single BrdU ( exhibitreducednumbersofperitonealmacrophages,whichcould pulse were 7 and 15-fold lower than those found in HSC and beexplainedbytheperturbationintheirmetabolism,culminating GMP, respectively. Moreover, the presence of BrdU LPMs was in the high frequency of cell death found in this compartment detectable 14days after BrdU pulse, suggesting that they are a (77). Despite great contributions to our understanding in the Frontiers in Immunology | www.frontiersin.org 4 May 2015 | Volume 6 | Article 225 Cassado et al. Peritoneal macrophage heterogeneity involvement of GATA-6 in peritoneal macrophage development, LPMs, SPMs, B-1 cells, conventional B-2 cells, T cells, NK cells, metabolism, self-maintenance, and survival, the existence of dis- DCs,andgranulocytes(mostlyeosinophils)(31,35).B1cellscon- tinctpathwaysthatcouldgovernthetranscriptionalregulationof stitutethemajorityofthePerCcellpopulation,whereastheSPM SPMsremainslargelyunknown. and LPM frequencies represent 30–35% of total peritoneal cells In addition to transcriptional regulation, signaling factors (31, 35) (Figure 2A). However, after inflammatory or infectious derived from the microenvironment also play an essential role stimuli, there is a dramatic alteration in cell numbers and the in promoting the development and phenotype of tissue-resident frequenciesofeachofPerCcellsubpopulation.Withregardtothe macrophages. For example, TGF-β1 signaling is required for myeloid compartment, modifications in PerC cell composition the development of the microglia population and to regulate a include the disappearance of LPMs, increases in SPM frequency microglia expression program through the Smad tissue factors andnumbers,andamassiverecruitmentofinflammatorymono- (78–80). Heme has been shown to induce Spi-c, a transcription cytes(24,31,35,36,40)(Figure2B). factor important for red pulp macrophage development (81, 82). The“macrophagedisappearancereaction”(MDR)inPerChas Finally, in PerC, omentum-derived RA promotes the expression been extensively described during delayed-type hypersensitivity of GATA-6 in the LPM subset, determining its localization and (DTH) and acute inflammatory processes (84). MDR has been functions (40), even if the factors that maintain the SPM pool associated with cell death, emigration to draining lymph nodes, understeadystateconditionsstillremaintobeelucidated. or adherence of macrophages to structural tissues. LPMs are the uniqueperitonealmacrophagesubsetthatdisappearsfromPerC, Dynamics and Function of Peritoneal which is attributed not to cell death but rather to their migration to the omentum (31, 40). LPM disappearance in response to Macrophage Subsets inflammatory stimuli is accompanied by an increase in SPM and Mouse PerC is a compartment where many cell types co-habitat inflammatorymonocytenumbers(24,31,35,36,40)(Figure2B), and interact, similar to the secondary lymphoid organs. In addi- and has been correlated with the renewal and improvement of tion, PerC is a unique body compartment that contains B-1 cells immune conditions of the PerC (35). Adherent peritoneal cells (83). Under steady state conditions, the peritoneal cells comprise from naive mice, which are composed primarily of LPM, exhibit FIGURE 2 | Summary of the dynamic of peritoneal macrophage from zymosan and T. cruzi stimulated mice contribute to effector function of PerC through secretion of high levels of NO and presence of IL-12-producing subsets. (A) Under homeostatic conditions, peritoneal macrophages comprise two subsets LPMs and SPMs (31). LPMs, which are the major cells (35). In response to LPS in vivo, SPMs produce several inflammatory cytokines, such as IL-12, MIP-1α, TNF-α, and RANTES, whereas LPMs peritoneal macrophage population, appear to be responsible for phagocytosis of apoptotic cell and tissue repair (36). (B) At the outset of inflammation, the produce enhanced amounts of G-CSF, GM-CSF, and KC (36). LPMs, which myeloid compartment is modified in general by disappearance of LPMs, migrate to omentum by a retinoic acid and GATA-6-dependent way in increase of SPMs numbers, and monocytes influx (31, 35, 36, 40). The response to in vivo LPS stimulation or vitamin-A deprivation, return to PerC changes in the myeloid cells from zymosan, T. cruzi, and LPS stimulated or and appear to be correlated with GALT-independent and TGF-β2-dependent thioglicollate-elicited PerC result in the gain of immune state (35, 36). SPMs IgA production by B-1 cells in the intestine (40). Frontiers in Immunology | www.frontiersin.org 5 May 2015 | Volume 6 | Article 225 Cassado et al. Peritoneal macrophage heterogeneity a high frequency of cells stained for β-galactosamine (β-gal), a assays, SPMs appear to develop an efficient profile to control infectionsasM1macrophages,whereasLPMsassumearoleinthe senescence marker (85–87). These cells are unable to secrete NO in response to LPS challenge (35). In contrast, adherent peri- maintenanceofPerCphysiologicalconditionsasM2oralternative macrophages. Despite the preserved phagocytic ability of LPMs, tonealcellsfromTrypanosomacruziorzymosan-stimulatedmice in which the main cell population constitutes SPMs and mono- higher numbers of zymosan and E. coli were found inside of low int + SPMsatearlytimepointsafteri.p.injection(31,35).Conversely, cytes (F4/80 MHCII Ly-6C ), respectively, display a signifi- cantreductioninthefrequencyofβ-gal-positivecellsandsecrete at 1h after challenge, LPMs appear to present a higher phago- high levels of NO in response to LPS (35). The frequency of IL- cytic index of apoptotic thymocytes in comparison to SPMs (36) 12-producing cells after in vitro LPS plus IFN-γ stimulation was (Figure2A). also higher within myelo-monocytic cells from mice exposed to In addition, it was recently demonstrated that LPMs have a unique ability to induce gut-associated lymphoid tissue zymosan and T. cruzi than the frequencies of IL-12-producing cells found in unstimulated mice (35). In response to Staphylo- (GALT)-independent IgA production by peritoneal B-1 cells (40) (Figure 2B). RA and TGF-β2 are the most critical factors coccusepidermidiscell-free(SES)supernatantinvivostimulation, low + F4/80 CD11b cells (consisting of SPMs and DCs) produced to induce IgA class switching, and the production of TGF-β2 is regulated by the Tgfb2 and Ltbp1 genes, which are expressed by enhancedlevelsofIL-1β,IL-1α,TNF-α,andIL-12inthepresence or absence of subsequent SES treatment (37). In contrast, the LPMsinaGATA-6-dependentmanner.Thisprocessisregulated by the abundant presence of RA in the omentum, which is supernatants of adherent cells from naïve mice treated with SES were found to contain high levels of MCP-1, MCP-1α, MIP- responsible for the induction of GATA-6 expression in LPMs that migrates to this tissue. The dynamic of LPM migration 1β, and G-CSF (37). It is important to note that 4days after thioglycollateinjection,peritonealcells,anextensivelystudiedcell betweenthePerCandtheomentumafterthestimulationofPerC population (88–91), also consist primarily of SPMs and inflam- is correlated with their disappearance and the return to basal numbers of LPMs later after stimulation with LPS, zymosan, matory monocytes (31, 40). The increase in SPM numbers and theinfluxofinflammatorymonocytesthatwillgiverisetoSPMs and thioglycollate (24, 31, 35, 36, 39, 40). This observation suggeststhatLPMscanreturntoPerCtoresolveaninfectiousor greatly contribute to the improvement of the capacity of PerC to deal with inflammatory stimuli. Indeed, although neither SPMs inflammatoryprocess.Therefore,thepresenceoftwospecialized macrophage subsets in PerC is crucial to maintain the health of norLPMsproducesignificantlevelsofpro-oranti-inflammatory cytokines under steady state conditions (35–37), SPMs appear to thiscompartmentunderdifferentsituations. developapro-inflammatoryprofileinresponsetoinvitrostimuli. SPMs produced high levels of TNF-α, MIP-1α, and RANTES in Concluding Remarks response to LPS, whereas LPMs were the unique population that producedabundantlevelsofG-CSF,GM-CSF,andKCinresponse Peritoneal macrophages represent one of the most studied tothesamestimulus(36)(Figure2B). macrophage populations. However, the existence of two pheno- The NO secretion and pro-inflammatory cytokine produc- typicallyandfunctionallydistinctsubsets,LPMsandSPMs,resid- tion are the most important functions of activated macrophages inginthePerCwasrecognizedrecently(31).Inthelastyear,great advances in our understanding of the transcriptional regulation by inflammatory stimulation and assigns the M1 profile (13, 34, 92–97). The functional profile of peritoneal macrophages of peritoneal macrophages have brought novel insights into the identification of LPMs and SPMs (39, 40). GATA-6, an LPM- was previous studied by our group and others (33, 34). Peri- tonealmacrophagesfromTh1-pronemousestrains(C57BL/6and restricted transcription factor, regulates many PMSGs, including thoserelatedtothemaintenanceofLPMsinPerC(40)andthose B10.A)areeasilyactivatedtoproduceNOinresponsetorIFN-γor LPS,characterizingtheM1profile.Incontrast,macrophagesfrom that determine their function (40), metabolism, proliferation, and cell survival (39, 77). Under steady state conditions, LPMs Th2-prone mouse strains (BALB/c and DBA/2) exhibit a weak NO response as a consequence of high levels of spontaneously appeartooriginateindependentlyfromhematopoieticprecursors secreted TGF-β1 (34). Moreover, the cells from C57BL/6 IL- and retained the ability to proliferate in situ, maintaining phys- 12p40-deficient mice have a bias toward the M2 profile, indi- iological numbers (26, 36). Conversely, SPMs appear to origi- cating that IL-12 is required for M1 polarization of peritoneal nate from circulating monocytes (31, 36, 40), and their numbers increase remarkably under inflammatory conditions. Of note, macrophages(33).AlthoughLPMsfromnaïvemicecanproduce NO afterin vitroLPS stimulation,SPMsproduce higherlevelsof SPMs together with their precursor, the inflammatory mono- cyte population, are the major myeloid populations present in NOthanLPMsfollowinginvivoLPSstimulation.TheNOsecre- tion by LPMs was also detected by flow cytometry in Escherichia elicitedPerC,andareanexcellentresourcetostudythebiologyof inflammatory macrophages. SPMs and LPMs exhibit specialized coliinoculatedmice(31),whereasnitritewasnotproducedinvitro by LPS-stimulated adherent peritoneal cells from control mice, functions in the PerC, where SPMs present a pro-inflammatory functionalprofile,andLPMsappeartohavearoleinthemainte- which is composed mainly by LPMs (35). In addition, adherent cellsobtained48hafterT.cruziinfection,whicharemostlycom- nance of PerC physiological conditions. Moreover, the particular interactionsbetweenmacrophagesubsetsandotherperitonealcell posed by SPMs, were the unique source of NO without in vitro subsequent challenge with LPS (35). In resume, the SPM and populations appear to play crucial roles in PerC immune state. LPMsubsetscannotbeaccommodatedintheM1/M2framework Although the consequences of the crosstalk between SPMs and considering the NO secretion. However, considering phagocytic peritonealTandBlymphocytesremaintobeclarified,LPMsare Frontiers in Immunology | www.frontiersin.org 6 May 2015 | Volume 6 | Article 225 Cassado et al. Peritoneal macrophage heterogeneity requiredfor GALT-independent andRA-dependent IgA produc- Acknowledgments tion by peritoneal B-1 cells (40). 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