Adipokines influence the inflammatory balance in autoimmunity

Cytokine xxx (2015) xxx–xxx

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Review Article

Adipokines influence the inflammatory balance in autoimmunity Jack Hutcheson ⇑ Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States

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Article history: Received 3 October 2014 Received in revised form 16 March 2015 Accepted 12 April 2015 Available online xxxx Keywords: Autoimmunity White adipose tissue Inflammation Adipokine

a b s t r a c t Over the past few decades, our understanding of the role of adipose tissue has changed dramatically. Far from simply being a site of energy storage or a modulator of the endocrine system, adipose tissue has emerged as an important regulator of multiple important processes including inflammation. Adipokines are a diverse family of soluble mediators with a range of specific actions on the immune response. Autoimmune diseases are perpetuated by chronic inflammatory responses but the exact etiology of these diseases remains elusive. While researchers continue to investigate these causes, millions of people continue to suffer from chronic diseases. To this end, an increased interest has developed in the connection between adipose tissue-secreted proteins that influence inflammation and the onset and perpetuation of autoimmunity. This review will focus on recent advances in adipokine research with specific attention on a subset of adipokines that have been associated with autoimmune diseases. Ó 2015 Elsevier Ltd. All rights reserved.

1. Introduction Mammals have at least two distinct types of adipose tissue. Traditionally, brown adipose tissue (BAT) was associated with energy expenditure and is responsible for thermogenesis to maintain appropriate body temperature, particularly in neonates while white adipose tissue (WAT) was traditionally considered to be primarily responsible for energy storage in the form of lipids [1]. This model was challenged by the discovery of adipsin and leptin, proteins secreted primarily from adipose tissue that impact homeostasis beyond the WAT environment [2,3]. In the years since these initial findings, it has become increasingly clear that adipocytes and other adipose tissue resident cells are responsible for secreting a wide array of additional proteins [4–12]. The earliest of these studies focused on the role of these secreted proteins in lipid metabolism and obesity, but the list of ‘‘adipokines’’ has now grown to encompass a number of additional processes, including pro-inflammatory as well as anti-inflammatory regulators [13,14]. Of note, WAT has been linked to at least 50 bioactive molecules [15], although not all of these may be produced specifically by adipocytes. For example, resident macrophages within adipose tissue may produce or contribute to the levels of certain cytokines and chemokines such as IL-1b, IL-6, CCL2 (MCP-1), TNFa and others, as macrophages have been identified as producers of these ⇑ Address: Department of Pathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9072, United States. Tel.: +1 214 648 5193; fax: +1 214 648 4067. E-mail address: [email protected]

mediators in other tissues [16]. Despite the fact that secretion of these cytokines is not exclusively confined to adipose tissue, WAT is an important site for the establishment of inflammation. For instance, some estimates suggest that as much as 30–35% of the systemic IL-6 production may be associated with WAT [17]. However, given the expanding prominence of obesity and adipokines as mediators of the inflammatory state, it is generally accepted to refer to all adipose tissue-secreted mediators as adipokines [18]. This scenario becomes even more poignant in light of the ongoing obesity epidemic where, intuitively, increased WAT leads to increased adipokine expression resulting in recruitment of additional cytokine-producing immune cells and further perpetuating the low-grade systemic inflammatory state present in those with chronic obesity [19]. Although it is clear that WAT is a significant source of IL-6, TNFa, and other traditional cytokines and chemokines, the immune functions of these mediators and their roles in autoimmunity are well documented [20,21]. As such, these mediators will not be specifically discussed in this review. It is worth noting that there is some evidence that BAT functions similarly to WAT in this regard, at least to some degree [22]. For instance, BAT produces cytokines, including IL-1a and IL-6, in response to thermogenic stimuli [23,24]. Given this evidence and the fact that phenotypic switching between WAT and BAT-like ‘‘beige adipocytes’’ is now well described [25–28], it is certainly conceivable that BAT-derived mediators impact similar processes as WAT-derived adipokines, however given the generally opposing metabolic natures of BAT and WAT [29], additional studies are necessary to further evaluate what impact BAT may have in this context.

http://dx.doi.org/10.1016/j.cyto.2015.04.004 1043-4666/Ó 2015 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Hutcheson J. Adipokines influence the inflammatory balance in autoimmunity. Cytokine (2015), http://dx.doi.org/ 10.1016/j.cyto.2015.04.004

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Autoimmune diseases are an extremely broad group of disorders that share little commonality other than that they all display abnormal immune responses against self-tissues or –proteins as a result of either dysregulation of T or B cell development or death, or an aberrant response to the antigen itself [30]. In turn, the affected tissue(s), severity, and outcome vary greatly depending on the localization and ubiquity of the self-antigen(s) and the underlying genetics of the specific disease [31]. As with immune responses directed against pathogenic insults, these immune responses are often associated with substantial inflammation [21]. Although an immune response and subsequent inflammatory response is designed to clear a pathogen and return to a homeostatic state, in autoimmunity the antigen is, by definition, native and thus unable to be eliminated. This can lead to chronic inflammation and eventual tissue destruction in one or more tissues or organ systems. While many individual autoimmune diseases are relatively uncommon, the entirety of the group of diseases impacts millions of people and presents a significant economic burden both in terms of health care costs as well as in lost productivity [32–35]. Despite the widespread overall impact of autoimmune diseases, effective biomarkers and therapeutic options for managing many of these conditions remain limited [36]. Thus, furthering our understanding of the inflammatory processes inherent to autoimmune diseases and how they are influenced by adipokines to perpetuate disease pathogenesis may help us limit disease severity or more effectively treat these conditions. Further, given the heterogeneous nature of autoimmune disorders, characterizing the shared as well as the disparate factors that contribute to specific diseases could help establish criteria to more effectively classify these diseases. 2. Adipose tissue and inflammatory autoimmunity Adipose tissue is comprised of a number of T cells and myeloid cells in addition to adipocytes [37]. In a lean state, the white adipose tissue is skewed towards an anti-inflammatory state. To this end, TH2 cells are the dominant T cell population and T regulatory cell (Treg), B regulatory cell (Breg), and invariant NKT cell populations are large enough to effectively suppress inflammation [37]. Increased adiposity results in higher numbers of immune cells associated with a pro-inflammatory phenotype, including TH17 cells [37–41]. Given that many autoimmune diseases are marked by ongoing inflammation, chronic obesity presents a predisposed systemic milieu to support the progression of autoimmune diseases. As such, it is not surprising that at least some reports have associated obesity with a higher risk or an increased disease activity in several inflammatory autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), Crohn’s disease, ulcerative colitis, and psoriasis [42–51]. Besides changing the immune cell composition of WAT, increased adiposity results in altered adipokine expression [1]. These adipokines include both anti- and pro-inflammatory regulators including traditional cytokines and chemokines, but also more conventional adipokines that are primarily produced in adipose tissue. The following adipokines, which represent only a small subset of identified adipokines, have recently been shown to be either associated with inflammatory autoimmune diseases (Fig. 1). 3. Leptin Leptin plays a critical role in regulating body weight by promoting satiety and increasing energy consumption [52]. Leptin-deficient mice (ob) are extremely obese and circulating leptin levels are correlated with WAT mass [42,53]. These mice are also immunodeficient, suggesting that leptin plays a critical role

in regulating the immune response [54]. Leptin acts as a pro-inflammatory mediator during both the innate and the adaptive immune response [15]. In innate immunity, leptin is involved in the production of pro-inflammatory molecules and immune signaling cascades related to neutrophil recruitment, macrophage activation and phagocytosis, activation of NK cells, and dendritic cell survival [55]. During the adaptive immunity, leptin skews T cells towards a pro-inflammatory phenotype by stimulating proliferation of leptin receptor-expressing T cells and skewing these cells towards a pro-inflammatory TH1 phenotype, and also by acting as a negative regulator of regulatory Tregs, which normally function to suppress autoimmunity [42]. Leptin acts as a counterbalance to other hormones, such as ghrelin, which trigger hunger [56]. Similar to their roles in metabolism, ghrelin and leptin also have offsetting roles in immunity [57]. These findings have further strengthened the link between metabolic hormones, adipokines and immune function. Leptin levels are also higher in females than males, even when corrected for confounding variables such as body mass index (BMI) [13]. This has led some to suggest that leptin may play a role in the influence of sex on the development of certain diseases including MS, and particularly SLE, which predominantly affect females [58]. Increased expression of leptin has been associated with multiple autoimmune diseases. Leptin-deficient mice develop a less severe form of antigen-induced arthritis characterized by diminished IFNc expression and increased IL-10 [59]. However, exogenous administration of leptin to leptin-deficient mice also sped disease resolution [60]. While these experiments provide little clarity, the data more consistently (but not unanimously) support that leptin expression is increased in RA patients and that the ratio of serum leptin to synovial fluid leptin is correlated with joint erosion [61,62]. In SLE, most evidence suggests that leptin is increased in patients, but is not directly associated with disease activity [63,64]. Leptin appears to be more influential in animal studies; in which leptin expression is higher in lupus-prone mice and lupus-prone leptin-deficient mice do not develop lupus [65]. Leptin-deficiency also protects otherwise susceptible mice from developing other experimentally-induced inflammatory diseases including colitis, type I diabetes, hepatitis, and experimental autoimmune encephalomyelitis (EAE), where administration of leptin results in a shift in T cell response and restores disease susceptibility [66]. Leptin is increased in MS patients and this is associated with increased levels of immune mediators including IFNc, TNFa and IL-1b and decreased Tregs [67,68]. Additionally, increased leptin expression has also been reported in Behçet’s disease [69], psoriasis [70], and during the acute phase of ulcerative colitis, but leptin levels are reportedly decreased in ankylosing spondylitis and ANCA-associated vasculitis [71–73]. Conflicting reports exist regarding the status of leptin in patients with systemic sclerosis [74–76]. Taken together, these reports demonstrate a potential role for leptin either in regulating disease pathogenesis or in response to disease onset across a wide spectrum of autoimmune diseases, although in many cases further study is necessary to determine the precise role of leptin in these diseases.

4. Adiponectin Comprised of multiple isoforms, adiponectin has the highest expression level of all adipokines and expression is decreased with obesity, suggesting that it functions differently than other adipokines [77]. Adiponectin reduces T cell responsiveness, B cell lymphopoiesis, and TNFa, but promotes IL-10 production [78–81]. Given these findings, the prevailing notion regarding adiponectin has been that it is an anti-inflammatory regulator; however, multiple studies have now demonstrated that it has pro-inflammatory

Please cite this article in press as: Hutcheson J. Adipokines influence the inflammatory balance in autoimmunity. Cytokine (2015), http://dx.doi.org/ 10.1016/j.cyto.2015.04.004

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Fig. 1. Adipokines associated with inflammation and autoimmune diseases. White adipose tissue (WAT) secretes a multitude of both pro- and anti-inflammatory adipokines and several of these have recently been associated with inflammation and autoimmunity in the literature. This figure presents an overview of our current understanding of these findings. Directional arrows represent either the impact on expression of the adipokine or the effect of the adipokine. A question mark denotes that the primary findings were in an animal model of the indicated disease. RA = rheumatoid arthritis, SLE = systemic lupus erythematosus, LN = lupus nephritis, MS = multiple sclerosis, Pso = psoriasis, PA = psoriatic arthritis, Sjo = Sjögren’s syndrome, AS = ankylosing spondylitis, T1D = type 1 diabetes, UC = ulcerative colitis, Cro = Crohn’s disease, IBD = inflammatory bowel disease, ANCA = ANCA-associated vasculitis, Beh = Behçet’s disease, Hep = autoimmune hepatitis.

roles as well including increasing expression and activity of pro-inflammatory mediators including MMP-3, MMP-9, IL-6, CCL2 and IL-8 [82–84]. While the cause of this discrepancy is not fully understood, it may be related to the differences between isoforms of adiponectin, with high molecular weight adiponectin acting primarily in an anti-inflammatory manner and the lower molecular weight isoform promoting a pro-inflammatory response, although these delineations ultimately remain to be elucidated [77]. This dichotomy in functions is evidenced in autoimmune diseases. Adiponectin levels are increased in both the serum and synovial fluid of RA patients and these measures are positively correlated with radiologic damage, disease activity, erythrocyte sedimentation rate, and rheumatoid factor [85,86]. Adiponectin levels also may be useful to predict disease progression in RA [87]. Adiponectin has also been found to be increased in ankylosing spondylitis, type I diabetes, and ulcerative colitis [88–91]. In mouse lupus models of SLE, decreased adiponectin is associated with increased renal damage [92,93]. Conversely, in SLE patients, multiple reports have demonstrated increased levels of adiponectin in patients’ serum, although there is little indication that this is associated with disease activity [63,94,95]. In multiple sclerosis, adiponectin levels are decreased in both mouse models and patient serum and this is associated with increased leukocyte activation levels and decreased Tregs [96,97]. Similarly in psoriasis, basal serum adiponectin levels were lower than healthy controls but increased with treatment [70,98,99]. Mice that develop sialoadenitis, a model for human Sjögren’s syndrome, exhibit lower levels of glandular adiponectin, but this is likely related to localized production of adiponectin [100]. Clearly there is significant evidence that adiponectin impacts inflammatory autoimmunity, but unraveling the role of adiponectin in this context will require a better understanding of the potentially opposing functions it plays in

inflammation, whether that is related to isoform differences or some other process.

5. Resistin While resistin was initially associated specifically with adipocytes, insulin resistance, and obesity in mice [101], human resistin is primarily produced by bone marrow-derived mononuclear cells [102] with some contribution from adipocytes [103]. Despite these differences between murine and human resistin, it is widely accepted that resistin is highly involved with promoting the inflammatory response [104]. Resistin can bind toll-like receptor 4 (TLR4) on human leukocytes leading to the production of pro-inflammatory cytokines including IL-12, IL-6, and IL-1b and, in turn, these cytokines further enhance resistin expression [102,105–107]. In vitro treatment with resistin produces a pro-inflammatory response from adipocytes (TNFa, IL-6, MCP-1), PBMCs (TNFa, IL-6, IL-1b), and hepatic stellate cells (IL-8, MCP-1) [104,108,109]. These effects on cytokine secretion are imparted through traditional NF-jB-mediated signaling [107,109]. Increased circulating resistin levels are correlated with markers of inflammation and joint destruction in RA and intra-articular injection of resistin may induce arthritis [104,110,111]. Conversely, anti-TNFa therapy sharply decreases resistin expression in RA [112]. Although reports regarding resistin expression in SLE vary, it has been suggested that resistin is indicative of active inflammation and active renal disease associated with SLE [64,113– 117]. Resistin levels were higher in patients with relapsing–remitting MS, ankylosing spondylitis, and psoriasis, and serum resistin is also correlated with inflammation in diabetes as well as Sjögren’s syndrome and inflammatory bowel disease [67,70,102, 118,119]. These data provide strong evidence suggesting that

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resistin may be a useful marker of general inflammatory status in autoimmunity and, given that the exogenous addition of resistin can induce inflammatory arthritis and that expression decreases upon treatment, may play a specific role in mediating autoimmune inflammation. 6. Visfatin Any roles for visfatin outside of its role as a mediator of inflammation are poorly understood, although there is some evidence that it exhibits insulin-like properties [120,121]. Visfatin was initially discovered in human peripheral blood lymphocytes and called pre-B cell colony-enhancing factor (PBEF) based on its ability to enhance pre-B-cell colony formation [122]. However, It has since been found that visfatin is largely produced by WAT, where it influences the production of both pro-inflammatory (IL-6, TNFa, and IL-1b) and anti-inflammatory (IL-10, IL-1RA) cytokines [122–126]. It also serves as a chemoattractant for both monocytes and lymphocytes and promotes expression of co-stimulatory molecules on monocytes, leading to increased T cell activation [127]. In RA, visfatin levels are increased both in circulation and in RA synovial fibroblasts and expression is correlated with disease severity and joint destruction [61,128,129]. Its expression is increased in response to pro-inflammatory stimuli and it leads to increased cytokine expression and the reinforcement of IL-6 production, in an autocrine fashion [130,131]. Furthermore, inhibition of visfatin function decreases disease severity in a mouse model of arthritis [132]. Visfatin expression is also increased in patients with relapsing–remitting MS [68] and psoriasis [70], as well as in ulcerative colitis and Crohn’s disease [133]. Given the correlation between visfatin levels and function and disease severity in RA, visfatin may be a useful biomarker for inflammation and disease progression. Whether this utility is specific to RA or more broadly applicable to the other autoimmune diseases in which increased visfatin levels have been found remains to be seen. 7. Chemerin Chemerin regulates the production of adipocytes and is strongly associated with increased BMI and metabolic syndrome [134–137]. Interestingly, despite the strong association between chemerin and WAT, the role of chemerin in autoimmune inflammation was observed before its identity as an adipokine was fully appreciated. Chemerin was initially isolated from the synovial fluid of RA patients, where it is positively correlated with disease activity and chemerin levels were decreased by anti-TNFa therapy [138– 140]. Serum chemerin levels are indicative of expression of pro-inflammatory cytokines including TNFa, IL-6, and C reactive protein [141,142]. The important role of chemerin in myeloid cell recruitment has been demonstrated in SLE, RA, and particularly in psoriasis, where chemerin recruits and activates plasmacytoid dendritic cells and is a potential biomarker of early lesion formation [143–148]. Chemerin is also increased in ulcerative colitis and Crohn’s disease where it influences inflammation by inhibiting anti-inflammatory macrophages [90,149]. In the EAE mouse model of multiple sclerosis, mice deficient for the chemerin receptor (CMKLR1) develop less severe disease, marked by decreased CNS inflammation, than control mice [150]. In MS patients, chemerin is associated with increased adiposity [151]. This suggests that obesity may play a role in enhancing inflammation in multiple sclerosis, although no other specific correlations were found for chemerin in disease activity [151]. Given that the importance of the chemerin-CMKLR1 axis has been demonstrated in multiple autoimmune diseases and that chemerin expression is highly associated with obesity, chemerin is an intriguing target to investigate

as additional studies examine the link between obesity and autoimmune inflammation.

8. Additional adipokines As mentioned in Section 1, more than 50 adipokines have been reported, of which this review has touched on only a handful that have recently been associated with autoimmunity. While these include some of the more studied adipokines, other adipokines have been begun to be associated with autoimmune diseases as well. Lipocalin-2 (NGAL), which is secreted from adipose in both humans and mice and regulates thermogenesis [152], activates and protects MMP-9 through the formation of heterodimers [153]. Lipocalin-2 is significantly increased in RA patient synovial fibroblasts as compared to osteoarthritis patients and is a candidate biomarker for lupus nephritis [153–156]. In RA, lipocalin-2 expression is induced by GM-CSF and negates the positive influence of EGF and FGF2 on chondrocyte proliferation, potentially promoting joint destruction [157]. In states of obesity, expression of hepcidin increases in adipose tissue [158]. Hepcidin acts as a regulator of iron homeostasis, but hepcidin expression is tied to inflammation. Under inflammatory conditions, hepcidin levels increase causing an influx of iron into macrophages, limiting erythropoiesis and contributing to states of systemic anemia, including anemia of chronic inflammation [15,159]. In mouse models of ulcerative colitis, increased hepcidin levels are the result of STAT3 activation by pro-inflammatory cytokines (e.g. IL-6) [160]. Hepcidin is increased in lupus nephritis and serves as a link between anemia and inflammation in patients with RA, where it has been correlated to atherosclerosis [161,162]. Omentin (intelectin-1) is recognized as a depot-specific adipokine whose gene expression and circulating levels are inversely related to obesity [163]. Omentin suppresses JNK activation by promoting AMPK/eNOS signaling and thus is an anti-inflammatory adipokine [164]. It also inhibits monocyte adhesion via inhibition of both ERK/NFjB and p38/JNK signaling [165,166] and has been further connected to innate immunity for its ability to recognize pathogenic galactofuranosyl residues and promote phagocytic clearance [167–169]. Recent studies have shown that omentin expression is decreased in Crohn’s disease (but not ulcerative colitis), psoriasis, and psoriatic arthritis [170– 172]. Sharing significant sequence homology with adiponectin [173] members of the C1q/tumor necrosis factor-a-related proteins (CTRPs), several of which have been identified as adipokines, display anti-inflammatory properties including inhibiting TLR4-induced inflammation and increasing IL-10 levels [174–176]. Mice lacking CTRP3 are more susceptible to collagen-induced arthritis, demonstrating that CTRP3 is an important factor in arthritis development. Further studies investigating the roles of other CTRP proteins in autoimmunity have not yet been reported, likely due to the relative novelty of the family as immune regulators. The link between these less established adipokines demonstrates two important points with regard to the role of adipokines in autoimmune inflammation. First, it demonstrates that although the link between adipokines and inflammation is now well established, the study of adipokines as immune regulators is still in its relative infancy. As further research in this area is pursued, it seems likely that new links will be made between existing adipokines and inflammatory diseases and that currently unknown adipokines that influence these processes will also continue to be uncovered. Secondly, it highlights the need for ongoing research in the area of autoimmunity. Whereas 15 years ago virtually no one would have considered that adipose tissue-derived proteins could influence autoimmune disease pathogenesis, so too must we can consider that additional pathways of

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immune regulation are likely contributing to autoimmune inflammation, whether they be related to adipose tissue, metabolism, or other as of yet unidentified processes. 9. Obesity and autoimmune diseases Given that a preponderance of evidence exists suggesting that adipokines can contribute to ongoing inflammation in autoimmune diseases, it would be natural to question to role that obesity may play in the onset or course of autoimmune diseases. To this end, obesity contributes to an increased risk or a more severe disease course in several autoimmune diseases including RA, MS, psoriasis, psoriatic arthritis, IBD, and SLE [42,46,177–180]. Given these associations, it seems possible that at least some patients suffering from autoimmune diseases may benefit from bariatric surgery to reduce the contribution of adipose tissue towards chronic immunity. Research in this area is sparse, largely because these patients have traditionally been counterindicated for bariatric procedures due to their extended use of steroids to treat the autoimmune conditions [181]. However, these procedures can be handled safely in patients with autoimmune diseases and, at least anecdotally, may impact disease severity to some degree [181]. 10. Conclusions While adipose tissue is known to play a vital role in regulating metabolic functions, our fundamental understanding of adipose tissue continues to evolve as new research develops regarding the roles of adipokines in regulating the immune response. While there is much left to learn, it is now clear that WAT can have a profound influence on inflammation. Given that autoimmune diseases are at least in part driven by unchecked inflammatory responses, it should perhaps come as no surprise that a wide array of adipokines contribute to the pathology of these diseases (Fig. 1). As we continue to explore the connections between adipokines, metabolic function, and immunity, WAT and the adipokine network have emerged as new targets in terms of biomarker discovery and may deserve increased attention with regards to potential therapeutic interventions. Acknowledgements I would like to thank Dr. Laurie Davis for assistance with proof reading this manuscript and Dr. Chandra Mohan for participating in scientific discussion in this area. This work was funded through departmental support from the University of Texas Southwestern Medical Center. References [1] Ouchi N, Parker JL, Lugus JJ, Walsh K. Adipokines in inflammation and metabolic disease. Nat Rev Immunol 2011;11:85–97. [2] Cook KS, Min HY, Johnson D, Chaplinsky RJ, Flier JS, Hunt CR, et al. Adipsin: a circulating serine protease homolog secreted by adipose tissue and sciatic nerve. Science 1987;237:402–5. [3] Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature 1994;372:425–32. [4] Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF. A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem 1995;270:26746–9. [5] Alvarez-Llamas G, Szalowska E, de Vries MP, Weening D, Landman K, Hoek A, et al. Characterization of the human visceral adipose tissue secretome. Mol Cell Proteomics 2007;6:589–600. [6] Aoki N, Jin-no S, Nakagawa Y, Asai N, Arakawa E, Tamura N, et al. Identification and characterization of microvesicles secreted by 3T3-L1 adipocytes: redox- and hormone-dependent induction of milk fat globuleepidermal growth factor 8-associated microvesicles. Endocrinology 2007; 148:3850–62.

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Please cite this article in press as: Hutcheson J. Adipokines influence the inflammatory balance in autoimmunity. Cytokine (2015), http://dx.doi.org/ 10.1016/j.cyto.2015.04.004