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IL-6 and the dysregulation of immune, bone, muscle, and metabolic homeostasis during spaceflight

IL-6 and the dysregulation of immune, bone, muscle, and metabolic homeostasis during spaceflight www.nature.com/npjmgrav REVIEW ARTICLE OPEN IL-6 and the dysregulation of immune, bone, muscle, and metabolic homeostasis during spaceflight John Kelly Smith We have previously reported that exercise-related secretion of IL-6 by peripheral blood mononuclear cells is proportionate to body weight, suggesting that IL-6 is gravisensitive and that suboptimal production of this key cytokine may contribute to homeostatic dysregulations that occur during spaceflight. This review details what is known about the role of this key cytokine in innate and adaptive immunity, hematopoiesis, and in bone, muscle and metabolic homeostasis on Earth and in the microgravity of space and suggests an experimental approach to confirm or disavow the role of IL-6 in space-related dysregulations. npj Microgravity (2018) 4:24 ; doi:10.1038/s41526-018-0057-9 INTRODUCTION stimulation by most nucleated cells, including monocytes, macrophages, endothelial cells, fibroblasts (main sources), In 2016, NASA’s Human Research Program solicited research to T cells, B cells, granulocytes, mast cells, myocytes, osteoblasts, help address health issues associated with spaceflight, including osteoclasts, osteocytes, chondrocytes, glial cells and keratinocytes. immune dysregulation and the risk of early onset osteoporosis The main cellular targets are hepatocytes, leukocytes, T cells, B and substandard performance due to reductions in muscle mass, cells, and hematopoietic cells. endurance, and strength. Binding of IL-6 to its transmembrane receptor (mIL-6R) leads to a Currently, high intensity resistance and aerobic exercises are complex consisting of two IL-6 molecules (homodimer), two IL-6R recognized as being the most effective countermeasures available proteins, and two glycoprotein 130 (gp130) molecules. Dimeriza- to astronauts to mitigate the adverse effects of microgravity on tion of gp130 activates cytokine receptor-associated Janus tyrosine bone and skeletal muscle. However, despite the implementation kinases (primarily Jak 1); in turn, the kinases activate cytoplasmic of high impact exercise training programs, unacceptable bone loss signal transducer and activator of transcription 3 (STAT3) which and muscle atrophy continue to occur during both short-term and dimerizes and translocates to the nucleus where it initiates extended spaceflight missions. transcription. The negative feedback of this signaling pathway is In a recent study involving 43 healthy adults, we found that regulated by suppressor-of-cytokine-signaling (SOCS) proteins 1 6 months of combined resistance and aerobic exercise training 6,7 and 3 and the protein inhibitors of activated STATs. diminished bone resorption and enhanced bone formation by Although expression of mIL-6R is restricted, being found changing the proportions of peripheral blood mononuclear cells primarily on hepatocytes and some leukocyte subsets, IL-6 also (PBMC) producing osteoclastogenic cytokines (interleukin (IL)-1α, interacts with soluble IL-6R (sIL-6R), which on binding to its tumor necrosis factor (TNF)-α, and interferon (IFN)-γ) and those ubiquitously expressed gp130 co-receptor can activate a variety of producing anti-osteoclastogenic cytokines (IL-4, IL-6, IL-10, and cells (IL-6 trans-signaling). During inflammation, mIL-6R is cleaved transforming growth factor (TFG)-β1). Notably, post-exercise by the metalloprotease ADAM 17 and shed as sIL-6R from increases in IL-6, a pleotropic cytokine involved in bone and 5 activated cells, markedly increasing IL-6 trans-signaling and muscle homeostasis and immune regulation, were proportionate 6,7 expanding the sphere of influence of this key cytokine. Low to body weight, a measure of one’s mass times the intensity of the 2 levels of soluble isoforms of IL-6-R and gp130 normally present in gravity field (9.8 /m/sec on Earth) (Fig. 1). This finding raises the blood serve to neutralize non-inflammatory levels of IL-6, thus possibility that the failure of exercise programs to attenuate bone protecting cells from overstimulation by IL-6 trans-signaling. and muscle loss in the microgravity of space is related to IL-6 trans-signaling is primarily responsible for the proinflam- suboptimal production of this important cytokine by postural matory activities of IL-6, whereas signaling via mIL-6R accounts for (antigravity) muscles and by bone cells and their supporting most of its anti-inflammatory and metabolic activities. mesenchymal and immune cell network. IL-6 AND IMMUNITY IL-6 On Earth IL-6 is a functionally pleiotropic growth and differentiation Innate immunity. In the early immune response, the source of IL- cytokine with context-dependent inflammatory and anti- 6 is primarily from innate immune cells activated by toll-like inflammatory properties; it plays an important regulatory role in receptor (TLR) binding of pathogen-associated molecular patterns innate and adaptive immunity, hematopoiesis, and in bone, (PAMPs) and by the secretion of IL-1α/β, TNF-α, IFN-γ, and/or muscle, and metabolic homeostasis. It is produced after Departments of Academic Affairs and Biomedical Sciences, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA Correspondence: John Kelly. Smith (smithj@etsu.edu) Received: 3 November 2017 Accepted: 10 October 2018 Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA IL-6 and the dysregulation of immune, bone, muscley JK Smith Fig. 1 Effect of body weight on IL-6 production by cultured peripheral blood mononuclear cells. This figure is from a publication on the effect of long-term exercise on peripheral blood mononuclear cell (PBMC) production of osteoclastogenic and anti-osteoclastogenic cytokines. a Spontaneous production of IL-6 by cultured PBMC (N = 41 subjects). b IL-6 production in PBMC cultures containing the T-cell mitogen phytohemagglutinin (PHA) (N = 41 subjects). c IL-6 production by PBMC of women in PHA + cultures (N = 23 subjects). d IL-6 production by PBMC of men in PHA + cultures (N = 18 subjects). (Linear regression analyses with 95% confidence intervals) granulocyte-macrophage colony stimulating factor (GM-CSF) by monocytes and macrophages by upregulating the expression of monocytes and macrophages. IL-6 usually enhances TLR- chemokines CCL4, CCL5, CCL11, CCL17 and intracellular and mediated cytokine and chemokine production; however, IL-1β, vascular adhesion molecules ICAM-1 and VCAM-1. It is an TNF-α, and IL-8 (CXCL8) production is suppressed by IL-6 when important growth and differentiation factor for activated naïve TLR4 binds its ligand, lipopolysaccharide (LPS), thus providing CD4 T cells: by upregulating their expression of nuclear factor of protection against endotoxemia. activated T cells (NFATc2) or SOCS1, IL-6 promotes IL-4-mediated IL-6 plays an important role in leukocyte trafficking and the Th2 cell differentiation or inhibits IFN-γ-mediated Th1 differ- transition from neutrophilic to monocytic infiltration at sites of entiation, respectively. With TGF-β as a cofactor, IL-6 drives the 9–11 inflammation. IL-6 trans-signaling promotes leukocyte recruit- differentiation of IL-21-producing Th17 cells; it can also convert ment to sites of acute inflammation by upregulating endothelial naturally occurring T regulatory (Treg) cells into Th17 cells and cell (EC) expression of intracellular adhesion molecule-1 (ICAM-1) increase Treg cell maturation by triggering the production of IL-27 9 19 and chemokines. By inducing monocyte expression of macro- by monocytes and macrophages. phage colony stimulating factor receptors, IL-6 promotes the IL-6 is also an important growth and differentiation factor for 6 + differentiation of monocytes to macrophages. It also can cause activated naïve CD8 T cells. It can trigger their differentiation dendritic cells to differentiate into macrophages and activate into IL-21-producing cells with activity against the influenza + 13 20 anti-inflammatory IL-10 M2-like (M2d) macrophages. virus and synergize with IL-15 or IL-7 to stimulate T-cell receptor (TCR) independent proliferation and effector func- Humoral immunity. IL-6 controls the proliferation, maturation and tions. In conjunction with IL-27 as a cofactor, IL-6 prompts the + + + survival of B cells and plasmablasts and initiates T-cell-dependent secretion of IL-10 by IFN-γ Th1, IL-4 Th2 and IL-17 Th17 cells. isotype switching and antibody production. In conjunction with IL- It also facilitates T-cell survival, inhibits TNF-α and IL-1β 1β as a cofactor, IL-6 prompts the differentiation of IL-10 B synthesis and induces IL-2 secretion and IL-2R expression in 6 + regulatory (B1) cells and triggers IL-21 production in CD4 T cells T cells. With IL-3 as a costimulant, IL-6 initiates the proliferation to drive STAT-3-dependent plasma cell development. IL-6 is of multipotential hematopoietic cells, including the maturation essential for T follicular cell (Tfh) differentiation; these cells are of megakaryocytes. critical to the ability of B cells to undergo isotype switching, terminal differentiation, and high affinity antibody production. Acute Phase Response. IL-6 synergizes with IL-1β, TNF-α, TGF-β, IL-8, and IL-22 to increase the production of acute phase proteins + 22 Cell-mediated immunity. IL-6 regulates the trafficking of CD4 (APP) by hepatocytes. APP such as C-reactive protein play a + 23 T cells, CD8 T cells, natural killer (NK) cells, dendritic cells, protective role at sites of inflammation and infection. npj Microgravity (2018) 24 Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA 1234567890():,; IL-6 and the dysregulation of immune, bone, muscley JK Smith IN SPACE waltl have shown that spaceflight can cause impaired antibody responses and changes in IgM heavy-chain transcription. Innate immunity Studies in humans. Studies on monocytes, macrophages, and Cell-Mediated Immunity TLRs done immediately after spaceflight have provided mixed results. Berendeeva and associates documented variable increases Studies in humans. Studies in astronauts have shown impaired in the relative and absolute counts of PBMC expressing TLR2, TLR4, delayed cutaneous hypersensitivity reactions and an increased and TLR6, findings like those described by Ponomarev et al. who incidence of herpes-group virus shedding during spaceflights. found an increase in serum levels of TLR2 and TLR4 ligands Crucian and associates found that virus-specificT-cellfunctionwas (HSP60, and HSP70 and HMG1, respectively) accompanied by an diminished in 19 astronauts during 10–15-day shuttle flights; they increase in the number of leukocytes expressing TLR2 and TLR4. also noted in-flight dysregulation of CD8 T-cell subsets and In contrast, Rykova reported a decrease in the levels of circulating diminished leukocyte secretion of IFN-γ,TNF-α,IL-10, IL-4, IL-5 and monocytes and granulocytes expressing TLR2, TLR4 and TLR6, IL-6 in response to PMA+ ionomycin; importantly, these authors accompanied by a reduction in TLR4-mediated LPS-induced noted significant differences in samples taken in-flight as compared cytokine production. to those taken post-flight. Other studies have documented post- + + Crucian and associates found that monocyte expression of cell flight reductions in blood levels of CD4 T cells, CD8 T cells, and surface markers important for antigen presentation (HLA-DR) and NK cells, increases in the proportion of T helper type 2 cells and for adhesion and tissue migration (CD62L) as well as the CD4/CD8 ratios, decreases in the cytotoxicity of NK cells, altered production of IL-6, IL-10 and TNF-α by LPS-stimulated monocytes plasma levels of cytokines, and variably impaired or enhanced were reduced following short-duration spaceflight. Importantly, secretion of Th-1 and Th-2-type cytokines in response to T-cell- 36,41–44 only IL-6 production was diminished in response to the pan- receptor-specificand/ornon-specificmitogens. leukocyte mitogen phorbol myristate acetate (PMA) + ionomy- cin. In a later study involving in-flight sampling, Crucian and Studies in rodents. In rodents, space travel decreases the masses associates found that IL-8 secretion was elevated in LPS- of lymph nodes, thymuses, and spleens and alters the distribution + + + stimulated monocytes but there was no statistically significant of CD3 , CD4 , and CD8 T cells and NK cells in blood, spleen, 37,38,45–47 change in the production of IL-12, TNF-α, IL-10, IL-6, or IL-1-β. and/or lymph nodes. Also documented are consistent 38,46-49 Compared to non-astronaut ground controls, Kaur and associ- decreases in mitogen-induced secretion of IL-2. Spaceflight ates found that intracellular levels of IL-6 and IL-1β were reduced and simulated microgravity have been shown to reduce IL-2, IL- and levels of IL-8 and IL-1 receptor antagonist (IL-1ra), were 2Rα, and IFN-γ gene expression and secretion in anti-CD3/CD28 increased in LPS-stimulated monocytes taken both before and antibody-activated mouse splenocytes. after spaceflight; except for IL-1-ra values returned to normal 6–12 months post-spaceflight. They also found that blood IL-6 AND BONE HOMEOSTASIS monocytes had a reduced ability to phagocytose Escherichia coli, elicit an oxidative burst, and degranulate; this impairment was On earth accompanied by a reduced expression of two surface markers IL-6 promotes bone formation by enhancing the differentiation of involved in phagocytosis, CD32 and CD64. osteoblasts precursors and by protecting osteoblasts from 51–55 apoptosis. It protects against bone resorption by decreasing Studies in rodents and drosophila. Studies on the effects of receptor activator of nuclear factor kappa B ligand (RANKL) spaceflight and simulated microgravity on murine splenocytes expression in osteoclasts, and by stimulating the production of the have also produced mixed results. Shen-An Hwang and associates anti-osteoclastogenic cytokines IL-4, IL-10, and IL-1 receptor found that a 13-day spaceflight increased the percent of dendritic antagonist while inhibiting the production of the osteoclastogenic cells expressing MHC I (CD11c MHC I) and the ability of splenic 56,57 cytokines IL-1-α/β and TNF-α by immune cells. IL-6 regulates macrophages to phagocytose fluorescent-tagged beads and to the expression of osteoprotegerin (OPG) in murine calvariae, and produce TNF-α when stimulated with a TLR-2 agonist but not is the main growth factor for B cells, the chief source of OPG in when stimulated with the TLR4 agonist LPS; IL-6 production was 31 bone marrow stroma; OPG is a potent inhibitor of osteoclasto- unchanged as compared to ground controls. In contrast, Wang genesis, and has recently been shown to reduce bone resorption et al. using simulated microgravity found that LPS-induced TNF-α when administered to mice during spaceflight. expression was impaired due to activation of heat shock factor-1, a IL-6 is produced in osteocytes and osteoblasts in response to known repressor of the TNF-α promoter. Also using simulated bone loading signals and plays an important role in bone microgravity, Brungs et al. found that splenic macrophages 61–63 remodeling. In murine osteoclasts, IL-6 binding to IL-6R and cultured with TLR-agonists had impaired production of reactive its coreceptor, gp130, releases osteoclast-derived coupling factors oxygen species (ROS) caused by diminished tyrosine kinase and osteotransmitters that protect bone by upregulating osteo- phosphorylation. Taylor and associates found that spaceflight blast activity. produced stress-related transcriptional responses that diminished the ability of Drosophila to mount a TLR-mediated response to fungal infection. In Space Space travel has been shown to accelerate astronaut bone loss to Humoral Immunity 1–1.6% per month, primarily in weight bearing bones ; this loss is associated with an increase in bone resorption and a decrease in Studies in humans. There are comparatively few studies on B-cell bone formation and has been attributed to the reduction in function in space. Voss found there no significant changes in bone-loading signals normally transduced by osteocytes resident serum immunoglobulin levels following a 10-day spaceflight and in the lacunar-canalicular network of bone. Researchers have Mills and associates found that mean circulating levels of CD19 B found that osteocyte apoptosis in trabecular and cortical bone cells increased in 11 astronauts following five 4–16-day shuttle occurs within 3 days of simulated weightlessness in mice and flights. precedes recruitment of osteoclasts. In addition, modeled Studies in rodents and amphibians. Spaceflight is reported to microgravity and hindlimb unloading has been shown to induce cause reductions in blood and splenic levels of B cells in osteoclast precursors to enhance RANKL-mediated 37,38 rodents. In addition, studies in the amphibian Pleurodeles osteoclastogenesis. Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA npj Microgravity (2018) 24 IL-6 and the dysregulation of immune, bone, muscley JK Smith Bone formation is reduced, and bone remodeling is impaired in heavy-chain isoforms. Gene expression of muscle-specific growth - - 70 IL-6 knockout (IL-6 / ) mice, and Harris and associates found that factors IL-6 and insulin-like growth factor (IGF)-1 was down- orbital spaceflight caused impaired osteoblast function associated regulated in soleus muscles and upregulated in EDL muscles. EDL with a reduction IL-6 mRNA expression. Using cultures of murine muscles also upregulated gene expression of stress-related osteoblasts, osteocytes, osteoclast precursors, and compressive markers. They concluded that, in contrast to soleus muscles, EDL cyclic forces, Hao and associates found that IL-6 + sIL-6R increased muscles compensate for the effects of microgravity by increasing osteocyte-mediated osteoblast differentiation and inhibited the expression of IL-6 and IGF-1 and various stress proteins; they osteoclastogenesis and osteoclast differentiation under mechan- posited that IGF-1 and IL-6 may be good candidates to counter the ical loading via STAT3 and extracellular signal-regulated kinase adverse effects of space travel on antigravity muscles such as the (ERK) signaling pathways soleus. IL-6 AND METABOLIC HOMEOSTASIS IL-6 AND MUSCLE HOMEOSTASIS On Earth On Earth Central nervous system. When injected into the ventricles of IL-6, a myokine, plays an important role in energy homeostasis obese rats, IL-6 has been shown to restore the anorexigenic effects and repair and remodeling of skeletal muscle. It activates skeletal of insulin and leptin by promoting IL-10-mediated inhibition of I B muscle 5‘ adenosine monophosphate activated protein kinase kinase β/NFΚB signaling and endoplasmic reticulum stress (AMPK) and/or phosphatidylinositol-3-kinase (P13K), increasing responses. IL-6 knockout mice develop late-onset obesity and glucose uptake and mitochondrial oxidation of fatty acids and 73,74 glucose intolerance. enhancing exercise endurance. IL-6 also plays a “pivotal” role in the response of skeletal muscle Pancreas. Using wild-type and IL-6 knockout mice with type 1 to injury which is determined by both existing muscle fiber nuclei diabetes, Paula and associates found that exercise-induced (which are terminally differentiated) and by a population of multi- + 75 generation of IL-6 increased β-cell viability in cultured pancreatic potential Pax7 mononucleated satellites cells (SC). When tissue by reducing the proinflammatory effects of IL-1β and IFN-γ. activated, SC migrate to the site of injury or remodeling and, IL-6 has also been shown to increase insulin secretion by under the control of a network of transcription factors, proliferate 75,76 promoting the production of the anorexigenic incretin glucagon- and differentiate into myocytes. IL-6 MKO mice have reduced like peptide-1 (GLP-1) by intestinal L and alpha cells. levels of SC proliferation and muscle repair capacity, and Ring finger protein-13 (RNF-13) knockout mice have accelerated Liver. In diet-induced obese rodents, IL-6 increases mitochondrial skeletal muscle regeneration mediated in part by macrophage- β-oxidation of fatty acids in hepatocytes, alleviating hepatic secreted IL-6. IL-6 upregulates the secretion of IL-4 and IL-10 in steatosis. immune cells and both cytokines play a positive role in 75,78 myogenesis. By increasing IL-6 secretion by myocytes, exercise Adipocytes. Approximately one-third of IL-6 is estimated to has been shown to promote extracellular matrix reorganization originate from adipose tissue where its effects are largely anti- and stem cell accumulation in the skeletal muscle stem cell obesogenic and anti-inflammatory. IL-6 stimulates lipolysis and fat niche. oxidation in adipocytes, downregulates TLR4-induced TNF-α, IL- 8, and macrophage metalloproteinase-1 (MCP-1) production by In Space resident macrophages, and prevents mature onset obesity and In both humans and rodents, the primary effect of spaceflight on insulin resistance in mice. skeletal muscle is fiber atrophy resulting in a decline in peak force, power, and exercise tolerance ; the atrophy mainly involves T cells. Activated T cells undergo metabolic reprogramming that antigravity muscles such as the soleus. At a molecular level, promotes glycolytic flux and lactate production and increases the microgravity-induced atrophy is due to increased proteasome production of lipids, proteins, nucleic acids and other carbohy- activity coupled with a reduction in protein synthesis and drates. Mammalian target of rapamycin (mTOR) signaling pro- mitochondrial biogenesis. As noted above, IL-6 plays an motes Th1, Th2, and Th17 differentiation, whereas Treg cells are important role in muscle repair and myogenesis. generated when AMPK signaling is activated and mTOR activation + + Skeletal muscle-specific AMPKα1α2 knockout mice (mdKO) have is suppressed. Unlike effector CD4 and CD8 T cells, Tregs and reduced exercise performance and fatigue resistance, findings memory T cells oxidize fatty acids for fuel. Upon activation, T cells similar to those described in humans and rodents during space also express insulin and leptin receptors and become sensitive to flight. IL-6 knockout mice (IL-6 KO) and muscle-specific IL-6 insulin signaling and nutrient availability. Accumulation of knockout mice (IL-6 MKO) have similar decreases in exercise lactate and lactic acid at sites of inflammation has been shown + + tolerance, presumably due to a reduction in IL-6-mediated AMPK to differentially inhibit the motility of CD4 T cells and CD8 secretion by exercising muscle. The observation that weightless- T cells by their effects on subtype-specific transporters Sic5a12 ness impairs the ability of murine soleus muscles to oxidize free and Sic16a1, respectively. fatty acids suggests that IL-6-mediated AMPK activation is As previously noted, IL-6 stimulates AMPK activity in myocytes; impaired in weight bearing muscles during spaceflight. Normally it is unclear as to whether this also occurs in T cells. during prolonged exercise there is a shift from carbohydrate utilization to lipid oxidation, thereby enhancing exercise 84 In Space tolerance. Pancreas. Subclinical diabetogenic changes, including alterations In a study done on mice during a 91-day spaceflight, Sandona in insulin secretion, insulin sensitivity, glucose tolerance, and and associates found that soleus muscles lost ~35% of cross- metabolism of protein and amino acids occur during spaceflight sectional area whereas extensor digitorum longus (EDL) muscles and in simulated conditions of microgravity. Experiments in flight showed no atrophy. Soleus muscles underwent physiological and after flight, ground-based bedrest studies, and bioreactor and morphological transformations, changing to a faster, more studies of pancreatic islets of Langerhans indicate that the glycolytic phenotype, with reductions in the proportion of slow pancreas is unable to overcome peripheral insulin resistance and twitch type 1 and 2 A fibers, increases in the proportion of fast amino acid dysregulation that occurs during space flight. twitch 2X and 2B fibers, and corresponding changes in myosin npj Microgravity (2018) 24 Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA IL-6 and the dysregulation of immune, bone, muscley JK Smith Table 1. Pleiotropic effects of IL-6 TARGET EFFECT B cells Controls the proliferation, maturation and survival of B cells and plasmablasts; initiates T-cell-dependent and -independent isotype switching and antibody production; promotes the differentiation of IL-10 B regulatory (B1) cells [IL-1β], and IL-21 production in CD4 T cells to drive STAT-3 dependent plasma cell development. T cells Regulates trafficking of lymphocytes, monocytes and macrophages and initiates transition from granulocytic to mononuclear cell infiltration at sites of inflammation; upregulates expression of surface markers involved in antigen presentation and phagocytosis; promotes the differentiation of Th2 [IL-4], Th17 [TGF-β], Th22 [TNF-α], Treg [IL-27], and + + + Tfh [IL-21] cells; initiates the secretion of IL-10 by IFN-γ Th1, IL-4 Th2 and IL-17 Th17 cells [IL-27]; facilitates T-cell survival; inhibits Th1 differentiation [IFN-γ] and TNF-α and IL-1β secretion; enhances IL-2, IL-4, IL-10, IL-1ra secretion and IL-2R expression; stimulates TCR independent CD8 T-cell proliferation and effector functions [IL-7 or IL-15]. Monocytes, dendrocytes Promotes monocyte and dendrocyte to macrophage differentiation and IL-10 M2 macrophage (M2d) activation. Hematopoietic progenitors Promotes proliferation of multipotential hematopoietic cells, including the maturation of megakaryocytes [IL-3]. Hepatocytes Initiates acute phase protein synthesis. Bone Promotes bone formation by enhancing OB differentiation from mesenchymal cell precursors, by inhibiting OB apoptosis, and by augmenting immune cell secretion of IL-4, IL-10 and IL-1ra; inhibits bone resorption by decreasing OC RANKL expression, by upregulating OPG secretion in bone and B cells, and by inhibiting immune cell secretion of IL-1α/β and TNF-α; enhances OB activity in response to bone loading signals by releasing osteoclast-derived coupling factors/ transmitters. Muscle Increases glucose uptake and mitochondrial fatty acid oxidation by activating AMPK, P13K. Promotes myocyte differentiation, proliferation, and response to injury. Promotes post-exercise extracellular matrix reorganization and stem cell niche accumulation. Metabolic homeostasis Restores CNS sensitivity to insulin, leptin; prevents obesity, glucose intolerance; increases pancreatic beta cell viability and insulin secretion; induces lipolysis, fat oxidation in hepatocytes, adipocytes. Cytokines bracketed by [] act as essential cofactors AMPK 5′ adenosine monophosphate activated protein kinase, CNS central nervous system, G/M granulocyte/monocyte, IFN-γ interferon-γ, IL interleukin, IL-1ra interleukin-1 receptor antagonist, IL-2R interleukin 2 receptor, OB osteoblast, OC osteoclast, OPG osteoprotegerin, P13K phosphatidylinositol-3-kinase, RANKL receptor activator of nuclear factor kappa B ligand, TCR T-cell receptor, Th T helper, Tfh T follicular helper, TGF-β transforming growth factor-β, TNF-α tumor necrosis factor-α Liver. Pecaut and associates measured liver transcriptomics and was well tolerated, with no changes noted in temperature, heart metabolomics in female C57BL/6J mice after a 13-day flight on the rate, blood pressure, or plasma epinephrine levels. Plasma levels of space shuttle Atlantis. Although the livers were depleted of the anti-inflammatory cytokines IL-10 and IL-1ra increased glycogen, functional gene analysis revealed both an increase in significantly during the infusions (8-fold and 26-fold, respectively) glycogen synthesis and glycogenolysis, pathways that do not whereas there were no changes in plasma TNF- α levels; plasma normally occur simultaneously except in the glycogen-depleted cortisol levels also increased causing a transient neutrophilia and liver. They also noted an increase in hepatic fatty acid oxidation. lymphopenia. CRP levels rose 3 and 16 h post-infusion. In a study involving 18 healthy men receiving intravenous Adipocytes. Spaceflight is associated with bone marrow adipo- glycerol and palmitate, Van Hall and associates found that both genesis due to redirected morphogenesis of mesenchymal cells. low and high dose rhIL-6 stimulated lipolysis and fat oxidation. However, there is little in the literature documenting metabolic Those receiving low dose rhIL-6 had mean plasma levels of changes in adipocytes during spaceflight. 140 pg/mL and experienced no adverse side effects, whereas those receiving high dose rhIL-6 had mean plasma levels of 319 pg/mL and developed ~30 min of “chills and discomfort”. T cells Plasma levels of insulin and glucagon were unaffected, whereas Using in-flight experiments and blood from human donors, Chang plasma adrenalin levels increased in the high dose group. Cortisol and coworkers have shown that Con A and anti-CD28-stimulated levels rose in both treatment groups, retuning to base line within T-cell activation is impaired in microgravity due to down- 2 h post-infusion. In a study involving eight healthy men the regulation of Rel/NF-κB, CREB, and SRF gene targets. The TNF same group found that a 4-h infusion of low dose rhIL-6 (30 µg/h) pathway was the major early downstream effector pathway selectively stimulated lipolysis in skeletal muscle but not in inhibited, potentially contributing to ineffective proinflammatory 97 adipose tissue. Again, this dose of rhIL-6 was well tolerated. responses during spaceflight. The reader is referred to Table 1 for a summary of the pleiotropic effects of IL-6. Recombinant IL-6: effect and safety issues in humans The reader is referred to a comprehensive review by Kammüller on DISCUSSION safety issues raised by the use of recombinant human IL-6 (hrIL-6) as a therapeutic agent. Provided below are several studies on During spaceflight astronauts and cosmonauts experience a the immune and metabolic effects of rhIL-6 in humans using well unique set of stressors including the effects of microgravity, tolerated doses that achieve plasma levels similar to those suboptimal nutrition, social isolation, confinement, sleep depriva- reached during strenuous exercise. tion, deconditioning, atypical work environment, solar radiation, 28,40,102 Steensberg and associates administered recombinant human IL- and alterations in circadian rhythms. Also extant are pre- 6 (rhIL-6) intravenously at a rate of 30 µg/hour for three hours to and postflight stressors, most notably those associated with six healthy young men achieving plasma levels of ~140 pg/mL landing and the abrupt need to re-adapt to Earth’s gravity. And, (equivalent to levels obtained during strenuous exercise) which by necessity, studies on the immune system and bone and muscle declined to preinfusion levels within an hour post-infusion. rhIL-6 homeostasis have involved different flight times and variations in Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA npj Microgravity (2018) 24 IL-6 and the dysregulation of immune, bone, muscley JK Smith research protocols. In this regard, most space physiologists D-P Häder and associates in reviewing gravireceptors in identify the results of studies performed during long duration eukaryotes noted that many eukaryotes use a mass such as a orbital spaceflights as being much more analogous to future deep statolith or total cell content to operate on gravireceptors (in space missions than short duration shuttle missions. many cases a mechanosensitive ion channel) either by pulling or Despite these difficulties, studies have consistently shown that pressing on an element of the cytoskeleton, ultimately resulting in spaceflight is associated with immune dysregulation, including the activation or silencing of genes. In human cells, they noted a alterations in surface markers, tissue distribution, cytokine direct correlation between changes in the cytoskeleton and transcription alterations in microgravity and posit that the production, phagocytic capacity, and anti-viral activity of immune 24–50 adhesive interaction of the cytoskeleton with the extracellar cells, Also well documented are the accelerated losses in matrix is the basis for gravisensing. Whatever the mechanism, bone and muscle mass and the loss of muscle strength and 65–72,80–84 microgravity alters the expression of several transcription factors, endurance during spaceflight. including nuclear factor kappa-light-chain-enhancer of B cells (NF- We have previously reported that long-term moderate intensity kB); NF-kB upregulates IL-6 production in human lung epithelial exercise increases the proportion of PBMC producing anti- cells and smooth muscle cells when their cytoskeletons are inflammatory cytokines and cytokines with osteogenic and 108,109 subjected to mechanical stress or stretching. And cardiac myogenic properties, and that these changes are associated with muscle AMPK expression is downregulated in microgravity ;as reductions in serum markers of bone resorption, increases in noted previously, IL- 6 enhances exercise endurance by activating markers of bone formation, and improvements in exercise AMPK-mediated increases in glucose uptake and fat oxidation tolerance and muscle strength. Because PBMC constantly 73,74 within myocytes. circulate through the highly vascular networks of bone and muscle, they have the potential, supported by our findings, to influence the physiology and ontogeny of muscle cells, and CONCLUSION osteoclasts, osteoblasts, osteocytes, and their precursors. PBMC It is posited that secretion of IL-6 is particularly sensitive to preparations also contain multipotential stem cells capable of cytoskeletal derangements and extracellular adhesive changes differentiating into a variety of tissues, including myocytes and 103 that occur under the force of gravity on Earth and in the bone cells. microgravity of spaceflight, and that the adverse effect of In our study, IL-6 was the only cytokine whose secretion was spaceflight on immune, bone, muscle and metabolic homeostasis proportionate to body weight, a measurement of the force of is related, at least in part, to altered gravisensing and consequent gravity. In this regard, Wehland and associates, found that IL-6 suboptimal production of this key cytokine. secretion in human chondrocytes increased > 2-fold when the cells were cultured under conditions of hypergravity (1.8 g), and Future direction Ma and associates documented a significant increase in IL-6 gene activation in thyroid cancer cells cultured under similar levels of On Earth, plasma levels of IL-6 increase in an exponential fashion hypergravity. In contrast, IL-6 production by mitogen- (up to 100-fold) in response to exercise and decline rapidly in the stimulated human PBMC is reduced in the microgravity of long post-exercise period. The increase is related to exercise intensity, duration spaceflight, and short-duration space flight has been duration, the mass of muscle recruited and one’s endurance found to dysregulate monocyte phenotype and reduce LPS- capacity. Preflight and inflight studies measuring post-exercise stimulated monocyte expression of several cytokines, including IL- IL-6 plasma levels should be done to determine whether production of this key myokine/cytokine is reduced during 6; notably, in this study, only IL-6 secretion was reduced postflight spaceflight, in which case inflight administration of rhIL-6 may in blood leukocytes cultured in the presence of phorbol myristate prove useful in preventing some of the deleterious effects of and ionomycin. And, as previously noted, IL-6 gene expression in spaceflight, particularly on muscle and bone. murine soleus muscle has been shown to decrease in the microgravity of spaceflight, and spaceflight impairment in osteoblast function has been attributed to a reduction IL-6 mRNA 71 DATA AVAILABILITY expression. The data used in figure one are available from the author on request. As documented in this review, reductions in the secretion of IL-6 during spaceflight could adversely affect a variety of its immune functions. This includes: the expression of intracellular and surface ACKNOWLEDGEMENTS markers involved in leukocyte trafficking and the transition of We acknowledges the support of the Department of Academic Affairs, James H. neutrophilic to monophilic inflammatory responses; the expres- Quillen College of Medicine, East Tennessee State University, Johnson City, sion of surface markers involved in antigen presentation and Tennessee. phagocytosis; the augmentation of IL-2, IL-2R, IL-4, IL-10 and IL-1ra and inhibition of IL-1β and TNF-α production; the promotion of T and B-cell survival; the enhancement of T-cell-dependent and AUTHOR CONTRIBUTIONS -independent antibody production; the differentiation of mono- J.K.S. is solely responsible for the preparation of the manuscript. cytes, macrophages, dendritic cells, B cells, and plasmablasts; the initiation of the acute phase protein response and the prolifera- tion of multipotential hematopoietic cells, including the matura- ADDITIONAL INFORMATION tion of megakaryocytes, and, as a cofactor, the differentiation of Competing interests: The authors declare no competing interests. + + CD4 and CD8 T cells, Th1 and Th2 cells, Th17 cells, Tregs, Tfh 6,9–22,27 cells. 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IL-6 and the dysregulation of immune, bone, muscle, and metabolic homeostasis during spaceflight

Smith, John
npj Microgravity , Volume 4 (1) – Dec 4, 2018
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Life Sciences; Life Sciences, general; Classical and Continuum Physics; Biotechnology; Immunology; Space Sciences (including Extraterrestrial Physics, Space Exploration and Astronautics) ; Applied Microbiology
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Abstract

www.nature.com/npjmgrav REVIEW ARTICLE OPEN IL-6 and the dysregulation of immune, bone, muscle, and metabolic homeostasis during spaceflight John Kelly Smith We have previously reported that exercise-related secretion of IL-6 by peripheral blood mononuclear cells is proportionate to body weight, suggesting that IL-6 is gravisensitive and that suboptimal production of this key cytokine may contribute to homeostatic dysregulations that occur during spaceflight. This review details what is known about the role of this key cytokine in innate and adaptive immunity, hematopoiesis, and in bone, muscle and metabolic homeostasis on Earth and in the microgravity of space and suggests an experimental approach to confirm or disavow the role of IL-6 in space-related dysregulations. npj Microgravity (2018) 4:24 ; doi:10.1038/s41526-018-0057-9 INTRODUCTION stimulation by most nucleated cells, including monocytes, macrophages, endothelial cells, fibroblasts (main sources), In 2016, NASA’s Human Research Program solicited research to T cells, B cells, granulocytes, mast cells, myocytes, osteoblasts, help address health issues associated with spaceflight, including osteoclasts, osteocytes, chondrocytes, glial cells and keratinocytes. immune dysregulation and the risk of early onset osteoporosis The main cellular targets are hepatocytes, leukocytes, T cells, B and substandard performance due to reductions in muscle mass, cells, and hematopoietic cells. endurance, and strength. Binding of IL-6 to its transmembrane receptor (mIL-6R) leads to a Currently, high intensity resistance and aerobic exercises are complex consisting of two IL-6 molecules (homodimer), two IL-6R recognized as being the most effective countermeasures available proteins, and two glycoprotein 130 (gp130) molecules. Dimeriza- to astronauts to mitigate the adverse effects of microgravity on tion of gp130 activates cytokine receptor-associated Janus tyrosine bone and skeletal muscle. However, despite the implementation kinases (primarily Jak 1); in turn, the kinases activate cytoplasmic of high impact exercise training programs, unacceptable bone loss signal transducer and activator of transcription 3 (STAT3) which and muscle atrophy continue to occur during both short-term and dimerizes and translocates to the nucleus where it initiates extended spaceflight missions. transcription. The negative feedback of this signaling pathway is In a recent study involving 43 healthy adults, we found that regulated by suppressor-of-cytokine-signaling (SOCS) proteins 1 6 months of combined resistance and aerobic exercise training 6,7 and 3 and the protein inhibitors of activated STATs. diminished bone resorption and enhanced bone formation by Although expression of mIL-6R is restricted, being found changing the proportions of peripheral blood mononuclear cells primarily on hepatocytes and some leukocyte subsets, IL-6 also (PBMC) producing osteoclastogenic cytokines (interleukin (IL)-1α, interacts with soluble IL-6R (sIL-6R), which on binding to its tumor necrosis factor (TNF)-α, and interferon (IFN)-γ) and those ubiquitously expressed gp130 co-receptor can activate a variety of producing anti-osteoclastogenic cytokines (IL-4, IL-6, IL-10, and cells (IL-6 trans-signaling). During inflammation, mIL-6R is cleaved transforming growth factor (TFG)-β1). Notably, post-exercise by the metalloprotease ADAM 17 and shed as sIL-6R from increases in IL-6, a pleotropic cytokine involved in bone and 5 activated cells, markedly increasing IL-6 trans-signaling and muscle homeostasis and immune regulation, were proportionate 6,7 expanding the sphere of influence of this key cytokine. Low to body weight, a measure of one’s mass times the intensity of the 2 levels of soluble isoforms of IL-6-R and gp130 normally present in gravity field (9.8 /m/sec on Earth) (Fig. 1). This finding raises the blood serve to neutralize non-inflammatory levels of IL-6, thus possibility that the failure of exercise programs to attenuate bone protecting cells from overstimulation by IL-6 trans-signaling. and muscle loss in the microgravity of space is related to IL-6 trans-signaling is primarily responsible for the proinflam- suboptimal production of this important cytokine by postural matory activities of IL-6, whereas signaling via mIL-6R accounts for (antigravity) muscles and by bone cells and their supporting most of its anti-inflammatory and metabolic activities. mesenchymal and immune cell network. IL-6 AND IMMUNITY IL-6 On Earth IL-6 is a functionally pleiotropic growth and differentiation Innate immunity. In the early immune response, the source of IL- cytokine with context-dependent inflammatory and anti- 6 is primarily from innate immune cells activated by toll-like inflammatory properties; it plays an important regulatory role in receptor (TLR) binding of pathogen-associated molecular patterns innate and adaptive immunity, hematopoiesis, and in bone, (PAMPs) and by the secretion of IL-1α/β, TNF-α, IFN-γ, and/or muscle, and metabolic homeostasis. It is produced after Departments of Academic Affairs and Biomedical Sciences, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA Correspondence: John Kelly. Smith (smithj@etsu.edu) Received: 3 November 2017 Accepted: 10 October 2018 Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA IL-6 and the dysregulation of immune, bone, muscley JK Smith Fig. 1 Effect of body weight on IL-6 production by cultured peripheral blood mononuclear cells. This figure is from a publication on the effect of long-term exercise on peripheral blood mononuclear cell (PBMC) production of osteoclastogenic and anti-osteoclastogenic cytokines. a Spontaneous production of IL-6 by cultured PBMC (N = 41 subjects). b IL-6 production in PBMC cultures containing the T-cell mitogen phytohemagglutinin (PHA) (N = 41 subjects). c IL-6 production by PBMC of women in PHA + cultures (N = 23 subjects). d IL-6 production by PBMC of men in PHA + cultures (N = 18 subjects). (Linear regression analyses with 95% confidence intervals) granulocyte-macrophage colony stimulating factor (GM-CSF) by monocytes and macrophages by upregulating the expression of monocytes and macrophages. IL-6 usually enhances TLR- chemokines CCL4, CCL5, CCL11, CCL17 and intracellular and mediated cytokine and chemokine production; however, IL-1β, vascular adhesion molecules ICAM-1 and VCAM-1. It is an TNF-α, and IL-8 (CXCL8) production is suppressed by IL-6 when important growth and differentiation factor for activated naïve TLR4 binds its ligand, lipopolysaccharide (LPS), thus providing CD4 T cells: by upregulating their expression of nuclear factor of protection against endotoxemia. activated T cells (NFATc2) or SOCS1, IL-6 promotes IL-4-mediated IL-6 plays an important role in leukocyte trafficking and the Th2 cell differentiation or inhibits IFN-γ-mediated Th1 differ- transition from neutrophilic to monocytic infiltration at sites of entiation, respectively. With TGF-β as a cofactor, IL-6 drives the 9–11 inflammation. IL-6 trans-signaling promotes leukocyte recruit- differentiation of IL-21-producing Th17 cells; it can also convert ment to sites of acute inflammation by upregulating endothelial naturally occurring T regulatory (Treg) cells into Th17 cells and cell (EC) expression of intracellular adhesion molecule-1 (ICAM-1) increase Treg cell maturation by triggering the production of IL-27 9 19 and chemokines. By inducing monocyte expression of macro- by monocytes and macrophages. phage colony stimulating factor receptors, IL-6 promotes the IL-6 is also an important growth and differentiation factor for 6 + differentiation of monocytes to macrophages. It also can cause activated naïve CD8 T cells. It can trigger their differentiation dendritic cells to differentiate into macrophages and activate into IL-21-producing cells with activity against the influenza + 13 20 anti-inflammatory IL-10 M2-like (M2d) macrophages. virus and synergize with IL-15 or IL-7 to stimulate T-cell receptor (TCR) independent proliferation and effector func- Humoral immunity. IL-6 controls the proliferation, maturation and tions. In conjunction with IL-27 as a cofactor, IL-6 prompts the + + + survival of B cells and plasmablasts and initiates T-cell-dependent secretion of IL-10 by IFN-γ Th1, IL-4 Th2 and IL-17 Th17 cells. isotype switching and antibody production. In conjunction with IL- It also facilitates T-cell survival, inhibits TNF-α and IL-1β 1β as a cofactor, IL-6 prompts the differentiation of IL-10 B synthesis and induces IL-2 secretion and IL-2R expression in 6 + regulatory (B1) cells and triggers IL-21 production in CD4 T cells T cells. With IL-3 as a costimulant, IL-6 initiates the proliferation to drive STAT-3-dependent plasma cell development. IL-6 is of multipotential hematopoietic cells, including the maturation essential for T follicular cell (Tfh) differentiation; these cells are of megakaryocytes. critical to the ability of B cells to undergo isotype switching, terminal differentiation, and high affinity antibody production. Acute Phase Response. IL-6 synergizes with IL-1β, TNF-α, TGF-β, IL-8, and IL-22 to increase the production of acute phase proteins + 22 Cell-mediated immunity. IL-6 regulates the trafficking of CD4 (APP) by hepatocytes. APP such as C-reactive protein play a + 23 T cells, CD8 T cells, natural killer (NK) cells, dendritic cells, protective role at sites of inflammation and infection. npj Microgravity (2018) 24 Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA 1234567890():,; IL-6 and the dysregulation of immune, bone, muscley JK Smith IN SPACE waltl have shown that spaceflight can cause impaired antibody responses and changes in IgM heavy-chain transcription. Innate immunity Studies in humans. Studies on monocytes, macrophages, and Cell-Mediated Immunity TLRs done immediately after spaceflight have provided mixed results. Berendeeva and associates documented variable increases Studies in humans. Studies in astronauts have shown impaired in the relative and absolute counts of PBMC expressing TLR2, TLR4, delayed cutaneous hypersensitivity reactions and an increased and TLR6, findings like those described by Ponomarev et al. who incidence of herpes-group virus shedding during spaceflights. found an increase in serum levels of TLR2 and TLR4 ligands Crucian and associates found that virus-specificT-cellfunctionwas (HSP60, and HSP70 and HMG1, respectively) accompanied by an diminished in 19 astronauts during 10–15-day shuttle flights; they increase in the number of leukocytes expressing TLR2 and TLR4. also noted in-flight dysregulation of CD8 T-cell subsets and In contrast, Rykova reported a decrease in the levels of circulating diminished leukocyte secretion of IFN-γ,TNF-α,IL-10, IL-4, IL-5 and monocytes and granulocytes expressing TLR2, TLR4 and TLR6, IL-6 in response to PMA+ ionomycin; importantly, these authors accompanied by a reduction in TLR4-mediated LPS-induced noted significant differences in samples taken in-flight as compared cytokine production. to those taken post-flight. Other studies have documented post- + + Crucian and associates found that monocyte expression of cell flight reductions in blood levels of CD4 T cells, CD8 T cells, and surface markers important for antigen presentation (HLA-DR) and NK cells, increases in the proportion of T helper type 2 cells and for adhesion and tissue migration (CD62L) as well as the CD4/CD8 ratios, decreases in the cytotoxicity of NK cells, altered production of IL-6, IL-10 and TNF-α by LPS-stimulated monocytes plasma levels of cytokines, and variably impaired or enhanced were reduced following short-duration spaceflight. Importantly, secretion of Th-1 and Th-2-type cytokines in response to T-cell- 36,41–44 only IL-6 production was diminished in response to the pan- receptor-specificand/ornon-specificmitogens. leukocyte mitogen phorbol myristate acetate (PMA) + ionomy- cin. In a later study involving in-flight sampling, Crucian and Studies in rodents. In rodents, space travel decreases the masses associates found that IL-8 secretion was elevated in LPS- of lymph nodes, thymuses, and spleens and alters the distribution + + + stimulated monocytes but there was no statistically significant of CD3 , CD4 , and CD8 T cells and NK cells in blood, spleen, 37,38,45–47 change in the production of IL-12, TNF-α, IL-10, IL-6, or IL-1-β. and/or lymph nodes. Also documented are consistent 38,46-49 Compared to non-astronaut ground controls, Kaur and associ- decreases in mitogen-induced secretion of IL-2. Spaceflight ates found that intracellular levels of IL-6 and IL-1β were reduced and simulated microgravity have been shown to reduce IL-2, IL- and levels of IL-8 and IL-1 receptor antagonist (IL-1ra), were 2Rα, and IFN-γ gene expression and secretion in anti-CD3/CD28 increased in LPS-stimulated monocytes taken both before and antibody-activated mouse splenocytes. after spaceflight; except for IL-1-ra values returned to normal 6–12 months post-spaceflight. They also found that blood IL-6 AND BONE HOMEOSTASIS monocytes had a reduced ability to phagocytose Escherichia coli, elicit an oxidative burst, and degranulate; this impairment was On earth accompanied by a reduced expression of two surface markers IL-6 promotes bone formation by enhancing the differentiation of involved in phagocytosis, CD32 and CD64. osteoblasts precursors and by protecting osteoblasts from 51–55 apoptosis. It protects against bone resorption by decreasing Studies in rodents and drosophila. Studies on the effects of receptor activator of nuclear factor kappa B ligand (RANKL) spaceflight and simulated microgravity on murine splenocytes expression in osteoclasts, and by stimulating the production of the have also produced mixed results. Shen-An Hwang and associates anti-osteoclastogenic cytokines IL-4, IL-10, and IL-1 receptor found that a 13-day spaceflight increased the percent of dendritic antagonist while inhibiting the production of the osteoclastogenic cells expressing MHC I (CD11c MHC I) and the ability of splenic 56,57 cytokines IL-1-α/β and TNF-α by immune cells. IL-6 regulates macrophages to phagocytose fluorescent-tagged beads and to the expression of osteoprotegerin (OPG) in murine calvariae, and produce TNF-α when stimulated with a TLR-2 agonist but not is the main growth factor for B cells, the chief source of OPG in when stimulated with the TLR4 agonist LPS; IL-6 production was 31 bone marrow stroma; OPG is a potent inhibitor of osteoclasto- unchanged as compared to ground controls. In contrast, Wang genesis, and has recently been shown to reduce bone resorption et al. using simulated microgravity found that LPS-induced TNF-α when administered to mice during spaceflight. expression was impaired due to activation of heat shock factor-1, a IL-6 is produced in osteocytes and osteoblasts in response to known repressor of the TNF-α promoter. Also using simulated bone loading signals and plays an important role in bone microgravity, Brungs et al. found that splenic macrophages 61–63 remodeling. In murine osteoclasts, IL-6 binding to IL-6R and cultured with TLR-agonists had impaired production of reactive its coreceptor, gp130, releases osteoclast-derived coupling factors oxygen species (ROS) caused by diminished tyrosine kinase and osteotransmitters that protect bone by upregulating osteo- phosphorylation. Taylor and associates found that spaceflight blast activity. produced stress-related transcriptional responses that diminished the ability of Drosophila to mount a TLR-mediated response to fungal infection. In Space Space travel has been shown to accelerate astronaut bone loss to Humoral Immunity 1–1.6% per month, primarily in weight bearing bones ; this loss is associated with an increase in bone resorption and a decrease in Studies in humans. There are comparatively few studies on B-cell bone formation and has been attributed to the reduction in function in space. Voss found there no significant changes in bone-loading signals normally transduced by osteocytes resident serum immunoglobulin levels following a 10-day spaceflight and in the lacunar-canalicular network of bone. Researchers have Mills and associates found that mean circulating levels of CD19 B found that osteocyte apoptosis in trabecular and cortical bone cells increased in 11 astronauts following five 4–16-day shuttle occurs within 3 days of simulated weightlessness in mice and flights. precedes recruitment of osteoclasts. In addition, modeled Studies in rodents and amphibians. Spaceflight is reported to microgravity and hindlimb unloading has been shown to induce cause reductions in blood and splenic levels of B cells in osteoclast precursors to enhance RANKL-mediated 37,38 rodents. In addition, studies in the amphibian Pleurodeles osteoclastogenesis. Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA npj Microgravity (2018) 24 IL-6 and the dysregulation of immune, bone, muscley JK Smith Bone formation is reduced, and bone remodeling is impaired in heavy-chain isoforms. Gene expression of muscle-specific growth - - 70 IL-6 knockout (IL-6 / ) mice, and Harris and associates found that factors IL-6 and insulin-like growth factor (IGF)-1 was down- orbital spaceflight caused impaired osteoblast function associated regulated in soleus muscles and upregulated in EDL muscles. EDL with a reduction IL-6 mRNA expression. Using cultures of murine muscles also upregulated gene expression of stress-related osteoblasts, osteocytes, osteoclast precursors, and compressive markers. They concluded that, in contrast to soleus muscles, EDL cyclic forces, Hao and associates found that IL-6 + sIL-6R increased muscles compensate for the effects of microgravity by increasing osteocyte-mediated osteoblast differentiation and inhibited the expression of IL-6 and IGF-1 and various stress proteins; they osteoclastogenesis and osteoclast differentiation under mechan- posited that IGF-1 and IL-6 may be good candidates to counter the ical loading via STAT3 and extracellular signal-regulated kinase adverse effects of space travel on antigravity muscles such as the (ERK) signaling pathways soleus. IL-6 AND METABOLIC HOMEOSTASIS IL-6 AND MUSCLE HOMEOSTASIS On Earth On Earth Central nervous system. When injected into the ventricles of IL-6, a myokine, plays an important role in energy homeostasis obese rats, IL-6 has been shown to restore the anorexigenic effects and repair and remodeling of skeletal muscle. It activates skeletal of insulin and leptin by promoting IL-10-mediated inhibition of I B muscle 5‘ adenosine monophosphate activated protein kinase kinase β/NFΚB signaling and endoplasmic reticulum stress (AMPK) and/or phosphatidylinositol-3-kinase (P13K), increasing responses. IL-6 knockout mice develop late-onset obesity and glucose uptake and mitochondrial oxidation of fatty acids and 73,74 glucose intolerance. enhancing exercise endurance. IL-6 also plays a “pivotal” role in the response of skeletal muscle Pancreas. Using wild-type and IL-6 knockout mice with type 1 to injury which is determined by both existing muscle fiber nuclei diabetes, Paula and associates found that exercise-induced (which are terminally differentiated) and by a population of multi- + 75 generation of IL-6 increased β-cell viability in cultured pancreatic potential Pax7 mononucleated satellites cells (SC). When tissue by reducing the proinflammatory effects of IL-1β and IFN-γ. activated, SC migrate to the site of injury or remodeling and, IL-6 has also been shown to increase insulin secretion by under the control of a network of transcription factors, proliferate 75,76 promoting the production of the anorexigenic incretin glucagon- and differentiate into myocytes. IL-6 MKO mice have reduced like peptide-1 (GLP-1) by intestinal L and alpha cells. levels of SC proliferation and muscle repair capacity, and Ring finger protein-13 (RNF-13) knockout mice have accelerated Liver. In diet-induced obese rodents, IL-6 increases mitochondrial skeletal muscle regeneration mediated in part by macrophage- β-oxidation of fatty acids in hepatocytes, alleviating hepatic secreted IL-6. IL-6 upregulates the secretion of IL-4 and IL-10 in steatosis. immune cells and both cytokines play a positive role in 75,78 myogenesis. By increasing IL-6 secretion by myocytes, exercise Adipocytes. Approximately one-third of IL-6 is estimated to has been shown to promote extracellular matrix reorganization originate from adipose tissue where its effects are largely anti- and stem cell accumulation in the skeletal muscle stem cell obesogenic and anti-inflammatory. IL-6 stimulates lipolysis and fat niche. oxidation in adipocytes, downregulates TLR4-induced TNF-α, IL- 8, and macrophage metalloproteinase-1 (MCP-1) production by In Space resident macrophages, and prevents mature onset obesity and In both humans and rodents, the primary effect of spaceflight on insulin resistance in mice. skeletal muscle is fiber atrophy resulting in a decline in peak force, power, and exercise tolerance ; the atrophy mainly involves T cells. Activated T cells undergo metabolic reprogramming that antigravity muscles such as the soleus. At a molecular level, promotes glycolytic flux and lactate production and increases the microgravity-induced atrophy is due to increased proteasome production of lipids, proteins, nucleic acids and other carbohy- activity coupled with a reduction in protein synthesis and drates. Mammalian target of rapamycin (mTOR) signaling pro- mitochondrial biogenesis. As noted above, IL-6 plays an motes Th1, Th2, and Th17 differentiation, whereas Treg cells are important role in muscle repair and myogenesis. generated when AMPK signaling is activated and mTOR activation + + Skeletal muscle-specific AMPKα1α2 knockout mice (mdKO) have is suppressed. Unlike effector CD4 and CD8 T cells, Tregs and reduced exercise performance and fatigue resistance, findings memory T cells oxidize fatty acids for fuel. Upon activation, T cells similar to those described in humans and rodents during space also express insulin and leptin receptors and become sensitive to flight. IL-6 knockout mice (IL-6 KO) and muscle-specific IL-6 insulin signaling and nutrient availability. Accumulation of knockout mice (IL-6 MKO) have similar decreases in exercise lactate and lactic acid at sites of inflammation has been shown + + tolerance, presumably due to a reduction in IL-6-mediated AMPK to differentially inhibit the motility of CD4 T cells and CD8 secretion by exercising muscle. The observation that weightless- T cells by their effects on subtype-specific transporters Sic5a12 ness impairs the ability of murine soleus muscles to oxidize free and Sic16a1, respectively. fatty acids suggests that IL-6-mediated AMPK activation is As previously noted, IL-6 stimulates AMPK activity in myocytes; impaired in weight bearing muscles during spaceflight. Normally it is unclear as to whether this also occurs in T cells. during prolonged exercise there is a shift from carbohydrate utilization to lipid oxidation, thereby enhancing exercise 84 In Space tolerance. Pancreas. Subclinical diabetogenic changes, including alterations In a study done on mice during a 91-day spaceflight, Sandona in insulin secretion, insulin sensitivity, glucose tolerance, and and associates found that soleus muscles lost ~35% of cross- metabolism of protein and amino acids occur during spaceflight sectional area whereas extensor digitorum longus (EDL) muscles and in simulated conditions of microgravity. Experiments in flight showed no atrophy. Soleus muscles underwent physiological and after flight, ground-based bedrest studies, and bioreactor and morphological transformations, changing to a faster, more studies of pancreatic islets of Langerhans indicate that the glycolytic phenotype, with reductions in the proportion of slow pancreas is unable to overcome peripheral insulin resistance and twitch type 1 and 2 A fibers, increases in the proportion of fast amino acid dysregulation that occurs during space flight. twitch 2X and 2B fibers, and corresponding changes in myosin npj Microgravity (2018) 24 Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA IL-6 and the dysregulation of immune, bone, muscley JK Smith Table 1. Pleiotropic effects of IL-6 TARGET EFFECT B cells Controls the proliferation, maturation and survival of B cells and plasmablasts; initiates T-cell-dependent and -independent isotype switching and antibody production; promotes the differentiation of IL-10 B regulatory (B1) cells [IL-1β], and IL-21 production in CD4 T cells to drive STAT-3 dependent plasma cell development. T cells Regulates trafficking of lymphocytes, monocytes and macrophages and initiates transition from granulocytic to mononuclear cell infiltration at sites of inflammation; upregulates expression of surface markers involved in antigen presentation and phagocytosis; promotes the differentiation of Th2 [IL-4], Th17 [TGF-β], Th22 [TNF-α], Treg [IL-27], and + + + Tfh [IL-21] cells; initiates the secretion of IL-10 by IFN-γ Th1, IL-4 Th2 and IL-17 Th17 cells [IL-27]; facilitates T-cell survival; inhibits Th1 differentiation [IFN-γ] and TNF-α and IL-1β secretion; enhances IL-2, IL-4, IL-10, IL-1ra secretion and IL-2R expression; stimulates TCR independent CD8 T-cell proliferation and effector functions [IL-7 or IL-15]. Monocytes, dendrocytes Promotes monocyte and dendrocyte to macrophage differentiation and IL-10 M2 macrophage (M2d) activation. Hematopoietic progenitors Promotes proliferation of multipotential hematopoietic cells, including the maturation of megakaryocytes [IL-3]. Hepatocytes Initiates acute phase protein synthesis. Bone Promotes bone formation by enhancing OB differentiation from mesenchymal cell precursors, by inhibiting OB apoptosis, and by augmenting immune cell secretion of IL-4, IL-10 and IL-1ra; inhibits bone resorption by decreasing OC RANKL expression, by upregulating OPG secretion in bone and B cells, and by inhibiting immune cell secretion of IL-1α/β and TNF-α; enhances OB activity in response to bone loading signals by releasing osteoclast-derived coupling factors/ transmitters. Muscle Increases glucose uptake and mitochondrial fatty acid oxidation by activating AMPK, P13K. Promotes myocyte differentiation, proliferation, and response to injury. Promotes post-exercise extracellular matrix reorganization and stem cell niche accumulation. Metabolic homeostasis Restores CNS sensitivity to insulin, leptin; prevents obesity, glucose intolerance; increases pancreatic beta cell viability and insulin secretion; induces lipolysis, fat oxidation in hepatocytes, adipocytes. Cytokines bracketed by [] act as essential cofactors AMPK 5′ adenosine monophosphate activated protein kinase, CNS central nervous system, G/M granulocyte/monocyte, IFN-γ interferon-γ, IL interleukin, IL-1ra interleukin-1 receptor antagonist, IL-2R interleukin 2 receptor, OB osteoblast, OC osteoclast, OPG osteoprotegerin, P13K phosphatidylinositol-3-kinase, RANKL receptor activator of nuclear factor kappa B ligand, TCR T-cell receptor, Th T helper, Tfh T follicular helper, TGF-β transforming growth factor-β, TNF-α tumor necrosis factor-α Liver. Pecaut and associates measured liver transcriptomics and was well tolerated, with no changes noted in temperature, heart metabolomics in female C57BL/6J mice after a 13-day flight on the rate, blood pressure, or plasma epinephrine levels. Plasma levels of space shuttle Atlantis. Although the livers were depleted of the anti-inflammatory cytokines IL-10 and IL-1ra increased glycogen, functional gene analysis revealed both an increase in significantly during the infusions (8-fold and 26-fold, respectively) glycogen synthesis and glycogenolysis, pathways that do not whereas there were no changes in plasma TNF- α levels; plasma normally occur simultaneously except in the glycogen-depleted cortisol levels also increased causing a transient neutrophilia and liver. They also noted an increase in hepatic fatty acid oxidation. lymphopenia. CRP levels rose 3 and 16 h post-infusion. In a study involving 18 healthy men receiving intravenous Adipocytes. Spaceflight is associated with bone marrow adipo- glycerol and palmitate, Van Hall and associates found that both genesis due to redirected morphogenesis of mesenchymal cells. low and high dose rhIL-6 stimulated lipolysis and fat oxidation. However, there is little in the literature documenting metabolic Those receiving low dose rhIL-6 had mean plasma levels of changes in adipocytes during spaceflight. 140 pg/mL and experienced no adverse side effects, whereas those receiving high dose rhIL-6 had mean plasma levels of 319 pg/mL and developed ~30 min of “chills and discomfort”. T cells Plasma levels of insulin and glucagon were unaffected, whereas Using in-flight experiments and blood from human donors, Chang plasma adrenalin levels increased in the high dose group. Cortisol and coworkers have shown that Con A and anti-CD28-stimulated levels rose in both treatment groups, retuning to base line within T-cell activation is impaired in microgravity due to down- 2 h post-infusion. In a study involving eight healthy men the regulation of Rel/NF-κB, CREB, and SRF gene targets. The TNF same group found that a 4-h infusion of low dose rhIL-6 (30 µg/h) pathway was the major early downstream effector pathway selectively stimulated lipolysis in skeletal muscle but not in inhibited, potentially contributing to ineffective proinflammatory 97 adipose tissue. Again, this dose of rhIL-6 was well tolerated. responses during spaceflight. The reader is referred to Table 1 for a summary of the pleiotropic effects of IL-6. Recombinant IL-6: effect and safety issues in humans The reader is referred to a comprehensive review by Kammüller on DISCUSSION safety issues raised by the use of recombinant human IL-6 (hrIL-6) as a therapeutic agent. Provided below are several studies on During spaceflight astronauts and cosmonauts experience a the immune and metabolic effects of rhIL-6 in humans using well unique set of stressors including the effects of microgravity, tolerated doses that achieve plasma levels similar to those suboptimal nutrition, social isolation, confinement, sleep depriva- reached during strenuous exercise. tion, deconditioning, atypical work environment, solar radiation, 28,40,102 Steensberg and associates administered recombinant human IL- and alterations in circadian rhythms. Also extant are pre- 6 (rhIL-6) intravenously at a rate of 30 µg/hour for three hours to and postflight stressors, most notably those associated with six healthy young men achieving plasma levels of ~140 pg/mL landing and the abrupt need to re-adapt to Earth’s gravity. And, (equivalent to levels obtained during strenuous exercise) which by necessity, studies on the immune system and bone and muscle declined to preinfusion levels within an hour post-infusion. rhIL-6 homeostasis have involved different flight times and variations in Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA npj Microgravity (2018) 24 IL-6 and the dysregulation of immune, bone, muscley JK Smith research protocols. In this regard, most space physiologists D-P Häder and associates in reviewing gravireceptors in identify the results of studies performed during long duration eukaryotes noted that many eukaryotes use a mass such as a orbital spaceflights as being much more analogous to future deep statolith or total cell content to operate on gravireceptors (in space missions than short duration shuttle missions. many cases a mechanosensitive ion channel) either by pulling or Despite these difficulties, studies have consistently shown that pressing on an element of the cytoskeleton, ultimately resulting in spaceflight is associated with immune dysregulation, including the activation or silencing of genes. In human cells, they noted a alterations in surface markers, tissue distribution, cytokine direct correlation between changes in the cytoskeleton and transcription alterations in microgravity and posit that the production, phagocytic capacity, and anti-viral activity of immune 24–50 adhesive interaction of the cytoskeleton with the extracellar cells, Also well documented are the accelerated losses in matrix is the basis for gravisensing. Whatever the mechanism, bone and muscle mass and the loss of muscle strength and 65–72,80–84 microgravity alters the expression of several transcription factors, endurance during spaceflight. including nuclear factor kappa-light-chain-enhancer of B cells (NF- We have previously reported that long-term moderate intensity kB); NF-kB upregulates IL-6 production in human lung epithelial exercise increases the proportion of PBMC producing anti- cells and smooth muscle cells when their cytoskeletons are inflammatory cytokines and cytokines with osteogenic and 108,109 subjected to mechanical stress or stretching. And cardiac myogenic properties, and that these changes are associated with muscle AMPK expression is downregulated in microgravity ;as reductions in serum markers of bone resorption, increases in noted previously, IL- 6 enhances exercise endurance by activating markers of bone formation, and improvements in exercise AMPK-mediated increases in glucose uptake and fat oxidation tolerance and muscle strength. Because PBMC constantly 73,74 within myocytes. circulate through the highly vascular networks of bone and muscle, they have the potential, supported by our findings, to influence the physiology and ontogeny of muscle cells, and CONCLUSION osteoclasts, osteoblasts, osteocytes, and their precursors. PBMC It is posited that secretion of IL-6 is particularly sensitive to preparations also contain multipotential stem cells capable of cytoskeletal derangements and extracellular adhesive changes differentiating into a variety of tissues, including myocytes and 103 that occur under the force of gravity on Earth and in the bone cells. microgravity of spaceflight, and that the adverse effect of In our study, IL-6 was the only cytokine whose secretion was spaceflight on immune, bone, muscle and metabolic homeostasis proportionate to body weight, a measurement of the force of is related, at least in part, to altered gravisensing and consequent gravity. In this regard, Wehland and associates, found that IL-6 suboptimal production of this key cytokine. secretion in human chondrocytes increased > 2-fold when the cells were cultured under conditions of hypergravity (1.8 g), and Future direction Ma and associates documented a significant increase in IL-6 gene activation in thyroid cancer cells cultured under similar levels of On Earth, plasma levels of IL-6 increase in an exponential fashion hypergravity. In contrast, IL-6 production by mitogen- (up to 100-fold) in response to exercise and decline rapidly in the stimulated human PBMC is reduced in the microgravity of long post-exercise period. The increase is related to exercise intensity, duration spaceflight, and short-duration space flight has been duration, the mass of muscle recruited and one’s endurance found to dysregulate monocyte phenotype and reduce LPS- capacity. Preflight and inflight studies measuring post-exercise stimulated monocyte expression of several cytokines, including IL- IL-6 plasma levels should be done to determine whether production of this key myokine/cytokine is reduced during 6; notably, in this study, only IL-6 secretion was reduced postflight spaceflight, in which case inflight administration of rhIL-6 may in blood leukocytes cultured in the presence of phorbol myristate prove useful in preventing some of the deleterious effects of and ionomycin. And, as previously noted, IL-6 gene expression in spaceflight, particularly on muscle and bone. murine soleus muscle has been shown to decrease in the microgravity of spaceflight, and spaceflight impairment in osteoblast function has been attributed to a reduction IL-6 mRNA 71 DATA AVAILABILITY expression. The data used in figure one are available from the author on request. As documented in this review, reductions in the secretion of IL-6 during spaceflight could adversely affect a variety of its immune functions. This includes: the expression of intracellular and surface ACKNOWLEDGEMENTS markers involved in leukocyte trafficking and the transition of We acknowledges the support of the Department of Academic Affairs, James H. neutrophilic to monophilic inflammatory responses; the expres- Quillen College of Medicine, East Tennessee State University, Johnson City, sion of surface markers involved in antigen presentation and Tennessee. phagocytosis; the augmentation of IL-2, IL-2R, IL-4, IL-10 and IL-1ra and inhibition of IL-1β and TNF-α production; the promotion of T and B-cell survival; the enhancement of T-cell-dependent and AUTHOR CONTRIBUTIONS -independent antibody production; the differentiation of mono- J.K.S. is solely responsible for the preparation of the manuscript. cytes, macrophages, dendritic cells, B cells, and plasmablasts; the initiation of the acute phase protein response and the prolifera- tion of multipotential hematopoietic cells, including the matura- ADDITIONAL INFORMATION tion of megakaryocytes, and, as a cofactor, the differentiation of Competing interests: The authors declare no competing interests. + + CD4 and CD8 T cells, Th1 and Th2 cells, Th17 cells, Tregs, Tfh 6,9–22,27 cells. 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M. et al. Exercise increases pancreatic β-cell viability in a model of org/licenses/by/4.0/. type 1 diabetes through IL-6 signaling. FASEB J. 29, 1805–1816 (2015). 88. Ellingsgaard, H. et al. Interleukin-6 enhances insulin secretion by increasing © The Author(s) 2018 glucagon-like peptide-1 secretion from L cells and alpha cells. Nat. Med. 17, 1481–1489 (2011). npj Microgravity (2018) 24 Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA

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