- Email: [email protected]
Adipose tissue macrophages and their polarization in health and obesity
Cellular Immunology xxx (xxxx) xxx–xxx
Contents lists available at ScienceDirect
Cellular Immunology journal homepage: www.elsevier.com/locate/ycimm
Research paper
Adipose tissue macrophages and their polarization in health and obesity Leen Catryssea,b, Geert van Looa,b, a b
⁎
VIB Center for Inflammation Research, B-9052 Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, B-9052 Ghent, Belgium
A R T I C LE I N FO
A B S T R A C T
Keywords: Obesity Adipose tissue macrophages Macrophage polarization
Adipose tissue is a special tissue environment due to its high lipid content. Adipose tissue macrophages (ATMs) help maintain adipose tissue homeostasis in steady state by clearing dead adipocytes. However, adipose tissue changes drastically during obesity, resulting in a state of chronic low grade inflammation and a shift in the adipose immune landscape. In this review we will discuss how these changes influence the polarization of ATMs.
1. Introduction People gain weight when their energy intake exceeds the energy demand of their body. As a consequence, the excess energy is stored in the adipose tissue. However, adipose tissue is not just a neutral storage place for lipids, it is considered to be an endocrine organ that can secrete a wide range of hormones and adipokines that regulate systemic metabolism [1]. Adipose tissue is mostly composed of adipocytes, but it also contains resident immune cells that help maintain organ homeostasis. From these, adipose tissue macrophages (ATMs) are the most abundant leukocyte population, constituting around 5% of the adipose tissue in lean state, which increases dramatically in conditions of obesity both in humans and in mice (up to 50% of adipose tissue) [2]. Obesity is associated with a low grade inflammatory state, characterized by elevated serum levels of inflammatory mediators such as TNF and IL-1β, and the presence of circulating bacterial lipopolysaccharide (LPS), which induce inflammation in different metabolic tissues. In visceral fat, this is accompanied by a dramatic shift in the immune landscape with more pro-inflammatory immune cells inducing inflammatory responses. This shift is most apparent in ATMs, as these cells not only greatly expand in number, but also shift their phenotype from so-called alternatively activated ‘M2’ macrophages to classically activated ‘M1’ macrophages [3]. In lean conditions, ATMs express classical ‘M2’ genes such as IL-10, Mrc2, Ym1/Chi3l3 and Mgl1/2, while in obese fat ATMs mainly express pro-inflammatory genes such as IL-6 and Nos2, reminiscent of classical ‘M1’ macrophages [4]. In addition, both ATM populations can be distinguished based on the expression of surface markers, where in lean fat tissue the majority of ATMs express CD206, while in obese conditions M1-like macrophages accumulate and upregulate CD11c (Table 1). This distinction between both types of macrophages is also reflected in their location, as CD206+ M2
⁎
macrophages mostly reside interstitially in between the adipocytes, while CD11c+ M1 macrophages are mainly found in Crown Like Structures (CLS) [5]. According to the current hypothesis, this phenotypic switch of ATMs is believed to be crucial to promote the pro-inflammatory environment in obese adipose tissue, affecting insulin sensitivity in peripheral organs [6,7]. 2. ATMs regulate adipose tissue homeostasis in steady lean state Adipose tissue macrophages are the tissue resident macrophages of adipose tissue and they are important to help maintain tissue homeostasis in steady state. Their main function is to engulf dead adipocytes to help in the cellular turnover of these cells. In the lean state, ATMs occasionally form a CLS around a dying adipocyte, however, since adipocytes are much larger compared to ATMs, they are not able to engulf the entire adipocyte. To solve this, the ATMs form an extracellular acidic compartment around the dead adipocyte, by the release of their lysosomal enzymes through exocytosis, as shown in humans and in mice. As a result, the lysosomal enzymes liberate the free fatty acids (FFA), which are then taken up by the macrophages to be processed [8]. Interestingly, when adipocyte apoptosis is induced in mice, mostly alternatively activated CD206+ M2 macrophages are recruited [9]. This indicates that adipocyte death alone is not enough to drive the switch to more inflammatory M1 macrophages suggesting that other factors, including live adipokine-secreting adipocytes are necessary to sustain the inflammation in adipose tissue. Moreover, the process of CLS formation and the clean removal of dead adipocytes is considered to be beneficial for tissue homeostasis, but in obese conditions this system is clearly out of balance. Besides their role in the removal of dead adipocytes, ATMs also buffer part of the lipid pool present in the adipose tissue. When lipolysis
Corresponding author at: Center for Inflammation Research, VIB and Ghent University, Technologiepark 927, B-9052 Ghent, Belgium. E-mail address: [email protected] (G. van Loo).
https://doi.org/10.1016/j.cellimm.2018.03.001 Received 15 October 2017; Received in revised form 14 February 2018; Accepted 1 March 2018 0008-8749/ © 2018 Elsevier Inc. All rights reserved.
Please cite this article as: Catrysse, L., Cellular Immunology (2018), https://doi.org/10.1016/j.cellimm.2018.03.001
Cellular Immunology xxx (xxxx) xxx–xxx
L. Catrysse, G. van Loo
with the accumulation of lipid species in mouse ATMs, which coincides with the induction of gene-expression networks associated with lipid uptake, storage, and metabolism [12]. Interestingly, the lipid trafficking protein fatty acid transport protein 1 (FATP1) in mouse macrophages was shown to play a critical role in suppressing macrophage activation and adipocyte inflammation through modulation of glucose metabolism and oxidative stress, identifying FATP1 as a regulator of immunometabolism [13]. Further research on lipid buffering and macrophage polarization in the context of obesity would be important to fully understand the metabolic changes in adipose macrophages and its resulting consequences. Recently, a lot of research has been done on the role of immune cells and the process of non-shivering thermogenesis or browning. In the current hypothesis it is believed that thermogenesis is activated by the joint interaction of eosinophils and type 2 Innate Lymphoid Cells (ILC2), leading to the alternative activation of ATMs, which start secreting catecholamines to induce the expression of thermogenic genes in brown adipose tissue (BAT) and lipolysis in white adipose tissue (WAT) of mice [14]. Depletion of alternatively activated ATMs impairs the thermogenic response to cold, while IL4 induces catecholamine synthesis, triglyceride lipolysis and thermogenic gene expression in adipocytes [14]. However, this hypothesis has recently been challenged, since the deletion of tyrosine hydroxylase, a key enzyme in the catecholamine synthesis pathway, in hematopoietic cells was shown to have no effect on thermogenesis upon cold exposure in mice [15]. Interestingly, another recent study showed that M1 ATMs express α4 integrin, which interacts with VCAM-1 on adipocytes of the
Table 1 Markers for adipose tissue macrophages.
Mouse
Human
ATMs
M1 ATMs
M2 ATMs
CD45+ CD11b+ F4/80+
CD11c+
CD206+ Optional: CD301+ Arginase 1+
Optional: CD64+ Siglec F− Ly6G− Ly6C− CD68+ CD14+
Optional: MHCII+ iNOS+
CD11c+
CD163+ Optional: CD204+ CD206+
is induced due to weight loss or starvation, ATMs get recruited to the adipose tissue, adopt an anti-inflammatory phenotype and take up the released lipids [10]. Hence, when macrophages are depleted from the abdomen and lipolysis is induced in mice, FFA levels in the serum rise extensively. These findings demonstrate that local lipid fluxes regulate ATM recruitment to buffer local increases in lipid concentration [10]. In obese conditions, the macrophages in the CLS also contain multiple lipid droplets and resemble foam cells, both in human and murine adipose tissue, however, here the lipid buffering capacity is insufficient to cope with the nutrient overload [6,11]. M1 polarization is associated
Fig. 1. The adipocyte niche influences macrophage polarization. In lean adipose tissue the adipocytes are well vascularized, insulin sensitive and healthy. Adipocytes produce factors including adiponectin to promote the alternative activation of CD206+ ATMs (green), and as a response these ATMs produce beneficial cytokines including IL-10. CD206+ ATMs present lipid antigens through their CD1d receptor to NKT cells, which stimulates their proliferation and activation. In return, NKT cells stimulate CD206+ polarization by producing IL-4 and IL10. Regulatory T cells also produce the beneficial IL-10 and in vitro assays suggest that CD11c+ ATMs can inhibit Treg differentiation, leading to their reduction in obesity. In lean adipose tissue, ILC1s have recently been shown to kill damaged CD206+ ATMs. Eosinophils and ILC2s work together to stimulate M2 polarization, through the production of IL-4 and IL-5/IL-13, respectively. In obese adipose tissue, the immune landscape changes drastically with more pro-inflammatory immune cells. Also, adipocytes are hypoxic, insulin resistant and stressed. Pro-inflammatory CD11c+ ATMs (red) accumulate, due to the increased levels of FFA, pro-inflammatory cytokines, hypoxia and ER stress. These ATMs are typically found in crown like structures (CLS) around a dying adipocyte (grey). In addition, neutrophils accumulate and stimulate CD11c+ M1 polarization through the secretion of elastase. Furthermore, B cells secrete IgGs, especially around CLS, which stimulates pro-inflammatory ATM polarization, together with CD8+ T cells and IFN-γ producing Th1 T cells. Also NK cells accumulate, producing more pro-inflammatory mediators including TNF and MCP1. CD11c+ ATMs have also been found to stimulate NK cell accumulation and proliferation, through, for example, the production of IL-15. ILC1/2 (Innate Lymphoid Cells 1/2), NKT cells (Natural Killer T cells), NK cells (Natural Killer cells), FFA (Free Fatty Acids), IRE1α (Inositol-requiring enzyme 1), HIF-1α (Hypoxia-inducible factor-1).
2
Cellular Immunology xxx (xxxx) xxx–xxx
L. Catrysse, G. van Loo
macrophages and induce a pro-inflammatory environment [26,27]. Because the adipose tissue has to expand so rapidly during obesity, the vasculature cannot follow, causing hypoxia-mediated dysfunction of the adipose tissue. However, also ATMs suffer from this hypoxia. Absence of HIF-1α, a master regulator of hypoxic responses, in myeloid cells was shown to protect mice from HFD-induced inflammation, CLS formation, poor adipose tissue vascularization and systemic insulin resistance. Moreover, the HIF-1α-deficient M1 macrophages inhibit the expression of angiogenic factors in adipocytes [28]. These data identify macrophage HIF-1α as a strong promotor of adipose tissue inflammation and adipose tissue remodeling inducing insulin resistance. HIF-1α was also shown to specifically regulate gene expression of IL-1β and other HIF-1α-dependent inflammatory genes in mice [29,30]. ATM polarization is also affected by the lipid load which is much higher in obese conditions, as mentioned above. Indeed, exposure of mouse macrophages to Very Low-Density Lipoproteins (VLDLs) and short chain fatty acids induces the secretion of typical pro-inflammatory M1 cytokines [31,32]. In addition, FFA, whose circulating levels are increased in obesity, can activate TLR4 signaling in murine ATMs, indicative of M1 polarization [33]. Finally, also endoplasmic reticulum (ER) stress enhances macrophage activation. Inositol-requiring enzyme 1α (IRE1α) was recently shown to act as a critical switch governing M1-M2 macrophage polarization [34]. Mice with myeloid-specific IRE1α deficiency are completely protected from HFD-induced obesity and insulin resistance, due to a reduction in fat mass, increased energy expenditure and enhanced browning [34]. In agreement, deficiency of IRE1α was shown to promote M2 polarization of macrophages, and transcriptome analysis revealed that IRE1α downregulates IRF4 and KLF4 expression, both key regulators of M2 polarization [34]. Interestingly, the ATM polarization is not affected in the lean state, indicating that there are obesogenic factors including FFA and LPS that can activate IRE1α in macrophages.
subcutaneous white adipose tissue in both the human and mouse system, leading to the downregulation of the thermogenic program [16]. Genetic or pharmacological inactivation of α4 integrin does not affect adiposity, but improves the thermogenic capacity and insulin sensitivity of adipocytes due to a reduction in M1 macrophage infiltration and CLS formation. In obesity, M1 macrophages even stimulate adipocytes to upregulate VCAM1, suggesting a self-sustained inflammatory loop to impair beige adipogenesis and to aggravate insulin resistance [16]. Finally, a new mechanism has been proposed whereby ATMs regulate insulin action and systemic insulin sensitivity by secreting microRNA containing exosomes into the circulation [17]. MiRNA-155 is one of the miRNAs overexpressed in obese ATM exosomes, and was shown to inhibit insulin signaling through a mechanism most likely related to a direct suppression of its target gene PPARγ [17]. However, most probably, also other miRNAs within these exosomes may have functional roles. 3. What drives the phenotypic switch between M1 and M2 during obesity ? ATMs are important to maintain adipose tissue homeostasis, however, during obesity ATMs switch their homeostatic phenotype to a proinflammatory phenotype that drives the development of insulin resistance (Fig. 1). The anti-inflammatory M2 ATMs preserve adipocyte insulin sensitivity by the production of IL-10, which has been shown to directly counteract the negative effects of TNF [3,18]. On the other hand, the pro-inflammatory M1 ATMs found in obese adipose tissue produce inflammatory cytokines including TNF, contributing to the development of insulin resistance [19]. When CD11c+ ATMs are depleted using a mouse diphtheria toxin model, insulin sensitivity is restored, inflammatory cytokines are suppressed, while IL-10 expression is increased [20]. An important question here is what drives this macrophage polarization switch from M2 to M1 ATMs.
3.2. The interplay with other immune cells Next to its effect on ATMs, it is now clear that obesity affects all immune cell types in adipose tissue [35]. Many immune cell types, including neutrophils, B cells, CD8 T cells, and Natural Killer cells accumulate in adipose tissue upon obesity, while eosinophils, Regulatory T cells, Natural Killer T cells and Type 2 Innate Lymphoid Cells decrease in numbers in obese conditions (Fig. 1).
3.1. Obese adipose tissue: a specific niche Adipose tissue is a special environment, unlike other organs in the body, because of its high fat content. In a lean state, ATMs are adapted to this specific situation. However, due to a chronic nutrient overload in conditions of obesity, adipocytes need to store excessive amounts of fat in a short time, causing a lot of adipocyte stress and eventually adipocyte death, explaining the increased number of CLS in obese adipose tissue. What type of adipocyte cell death occurs during obesity and how this influences ATM polarization is still unclear. Electron microscopy analysis of both human and mouse obese adipose tissue revealed ruptured adipocyte membranes and the presence of cellular debris, dilated endoplasmatic reticulum and small cytoplasmic lipid droplets, indicative of necrosis [6]. Interestingly, in both humans and mice, increased numbers of proliferating ATMs have been found preferentially in CLS regions, but independent of the activation state, suggesting that dying adipocytes secrete ATM proliferating factors [21,22]. However, additional studies using genetic approaches are needed to determine the type of adipocyte death that occurs during obesity, and how this influences ATM proliferation and activation. Adipocytes normally secrete the beneficial adipokine adiponectin, which stimulates M2 ATM polarization. In obesity however, adiponectin secretion is reduced, both in human and mouse models [23]. An important regulator for this could be the SIRTuin deacetylase SIRT1, which modulates the expression and secretion of several adipokines including adiponectin and IL-4 in mouse adipocytes, which in turn alters the recruitment and polarization of ATMs in adipose tissue maintaining insulin sensitivity [24]. Interestingly, SIRT1 undergoes proteolytic degradation in mouse adipose tissue upon prolonged HFD feeding exacerbating insulin resistance [25]. Obese adipocytes also secrete proinflammatory mediators including TNF and MCP1, which attract
3.2.1. Eosinophils The major IL-4 producing source in murine adipose tissue are eosinophils, which, through their production of IL-4 and IL-13, stimulate M2 ATM polarization [36]. In normal lean adipose tissue, the number of eosinophils account for 4–5% of the stromal vascular fraction, however, this decreases upon obesity, affecting the activation state of ATMs [36]. 3.2.2. Regulatory T cells About 10% of the stromal vascular fraction are regulatory T cells (Tregs) [37] which help maintain an anti-inflammatory environment by producing IL-10, thereby regulating insulin sensitivity in both humans and mice. In obese conditions however, Treg numbers are strongly reduced [38]. Although it is not known if Tregs interact with ATMs in vivo, in vitro assays have shown that media from classically activated M1 macrophages is able to inhibit Treg differentiation, while media from alternatively activated M2 macrophages does not [37], suggesting that the phenotypic switch seen in ATMs might contribute to the reduction in Treg cells in obesity. 3.2.3. Natural Killer T cells Natural Killer T (NKT) cells have important immunoregulatory functions also in adipose tissue, where they produce IL-4 and IL-10 and protect against diet-induced obesity in both humans and mice [39]. Their abundance in adipose tissue decreases with increasing adiposity 3
Cellular Immunology xxx (xxxx) xxx–xxx
L. Catrysse, G. van Loo
macrophage infiltration and adipose tissue inflammation [50]. Conversely, adoptive transfer of CD8+ T cells into CD8-deficient obese mice induces M1 macrophage infiltration and adipose tissue inflammation [50]. These data demonstrate that CD8+ T cells contribute to the propagation of adipose tissue inflammation and the development of insulin resistance in mice. In addition, increased numbers of IFN-γ producing Th1 cells have been found in both obese humans and mice, and in vitro studies showed that T cells from obese adipose tissue produce more IFN-γ, a potent stimulus to drive M1 polarization [51,52].
and insulin resistance. Specific activation of NKT cells via their lipid ligand α-galactosylceramide enhances anti-inflammatory gene expression in the adipose tissue and improves glucose homeostasis in an IL-4/ STAT6 dependent way [40]. Loss of CD1d in murine adipocytes reduces the number of NKT cells in the adipose tissue, resulting in an accumulation of M1 ATMs and a worsened insulin resistance [41]. NKT cell activation by M2 ATMs, however, stimulates Th2 responses and M2 polarization, and inhibits insulin resistance in mice [42]. Based on this, a model is proposed which suggests that an M2 ATM-specific reduction of CD1d is an initiating event that switches NKT cell-mediated immune responses and disrupts the immune balance in visceral adipose tissues in obese mice [42].
3.2.9. Natural Killer cells Natural Killer (NK) cells accumulate in adipose tissue and promote insulin resistance in obesity in mice. NK cell deletion reduces pro-inflammatory M1 ATM numbers, while NK cell expansion shows the opposite [53–55]. Interestingly, adipose NK cells control ATMs potentially by producing pro-inflammatory mediators, including TNF and MCP1. Also, obesity not only increases NK numbers, but it also makes them produce more TNF, most likely because obese ATMs produce more NK chemoattractants such as IL-15, which promotes NK cell activation and proliferation [53]. Importantly, gain or loss of NK cells has no effect in lean mice, indicating that the obesogenic environment is crucial for their function.
3.2.4. Type 1 Innate Lymphoid Cells 1 Type 1 Innate Lymphoid Cells (ILC1s) are enriched in human and mouse adipose tissue where their number rises in a short time period right after the onset of HFD feeding [43]. Interestingly, ILC1s are found in the proximity of stressed ATMs, marked by the expression of the stress ligand Rae-1, and are able to kill ATMs ex vivo, particularly M2 ATMs [43]. Depletion of adipose tissue ILC1s in lean mice results in alterations in the ratio of inflammatory to anti-inflammatory ATMs, and adoptive transfer of lean ILC1s exacerbated metabolic disease [43]. However, the ATM killing capacity of ILC1s is lost in conditions of obesity, indicating a role for ILC1s in regulating ATM homeostasis, which seems to be disturbed in obesity.
4. The M1/M2 paradigm: an oversimplification Obesity is generally characterized and described by the presence of an increased population of pro-inflammatory M1 ATMs that express CD11c, while lean adipose tissue by the presence of anti-inflammatory M2 ATMs that express CD206 and MGL1/2. However, this M1/M2 classification is an oversimplification, and macrophages display a more dynamic and varied spectrum of activation states in between the two extreme M1 and M2 classes [56]. The M1/M2 classification is entirely based on a very biased approach where only a specific set of pro- and anti-inflammatory genes is considered and is mostly based on studies done in mice. An unbiased approach such as a full transcriptome analysis gives a more objective view on the identity and function of ATMs and how these change during the course of obesity. Using such an unbiased transcriptome analysis on CD11c+ and CD11c− ATMs in different models of obesity, Xu et al. could not identify a prototype M1 signature associated with a classical inflammatory phenotype but, instead, a signature of lysosomal-dependent lipid metabolism [57]. The prototype expression of genes associated with classically activated, M1polarized macrophages or alternatively activated M2-polarized macrophages was not different between ATMs in lean and obese mice, arguing against a simple binary switch in ATMs in obesity [57]. The changes in the inflammatory profile of the adipose tissue in obesity rather reflect quantitative changes in the number of macrophages and other immune cell populations infiltrating the adipose tissue. Using a proteomics approach, Kratz et al. could also not identify the typical markers of classical M1 ATM activation in macrophages from obese humans, but again identified proteins that promote lipid metabolism [58]. These ‘omics’ approaches and new technologies including single cell RNA sequencing will be very helpful to identify and better characterize different ATM populations and their impact on metabolic changes in the adipose tissue.
3.2.5. Type 2 Innate Lymphoid Cells ILC2s promote the accumulation of eosinophils and M2 ATMs by providing a major source of IL-5 and IL-13 to murine adipose tissue [44]. Depletion of ILC2s in mice greatly reduces the number of eosinophils and M2 ATMs in adipose tissue [44]. ILC2s have also been shown to regulate thermogenesis and browning in mice, by producing methionine-enkephalin peptides [45]. In obesity, ILC2 levels decrease, hence their strong anti-inflammatory effects are lost [44,45]. Indeed, depletion of ILC2s in obese mice leads to exacerbation of weight gain and glucose intolerance, while transfer of ILC2 in obese mice promotes weight loss [46]. 3.2.6. Neutrophils Neutrophils are recruited to murine adipose tissue in conditions of obesity [47]. Neutrophil recruitment has a negative impact on the development of insulin resistance, mainly because of the proteases they secrete, one of which is neutrophil elastase. Deletion of neutrophil elastase in high-fat-diet–induced obese mice reduces adipose tissue inflammation and lowers adipose tissue neutrophil and macrophage content. These changes are accompanied by improved glucose tolerance and increased insulin sensitivity [48]. Since neutrophil elastase is able to induce M1 macrophage polarization in vitro, recruitment of neutrophils to adipose tissue is considered to be an important determinant in the polarization switch seen in ATMs. 3.2.7. B Cells B cells contribute to the development of insulin resistance, and mice lacking B cells have improved glucose homeostasis despite weight gain [49]. B cells promote T cell activation and pro-inflammatory cytokine production, which potentiate M1 macrophage polarization and insulin resistance. Besides, B cells also produce pathogenic IgG antibodies [49]. Murine crown like structures appear to be surrounded by tissue fluid enriched for IgM and IgG, and the Fc portion of IgG is able to activate ATMs to produce more TNF [49].
Conflict of interest The authors declare no conflict of interest. Acknowledgements
3.2.8. T cells Infiltration of CD8+ effector T cells is an early event during the development of obesity in mice and even precedes macrophage accumulation [50]. Deletion of CD8+ T cells in obese mice does not affect body weight, but ameliorates insulin resistance and lowers M1
L. Catrysse was supported as a PhD fellow by the “Instituut voor Innovatie door Wetenschap en Technologie” (IWT) and by a research grant from “Kom op tegen Kanker”. Research in the van Loo lab is supported by grants from VIB, the Fund for Scientific Research Flanders 4
Cellular Immunology xxx (xxxx) xxx–xxx
L. Catrysse, G. van Loo
(FWO), the Foundation against Cancer, the Queen Elisabeth Medical Foundation, the Charcot Foundation, and the Concerted Research Actions (GOA) of the Ghent University.
[19] O. Osborn, J.M. Olefsky, The cellular and signaling networks linking the immune system and metabolism in disease, Nat. Med. 18 (2012) 363–374, http://dx.doi. org/10.1038/nm.2627. [20] D. Patsouris, P.P. Li, D. Thapar, J. Chapman, J.M. Olefsky, J.G. Neels, Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals, Cell Metab. 8 (2008) 301–309, http://dx.doi.org/10.1016/j.cmet.2008.08. 015. [21] S.U. Amano, J.L. Cohen, P. Vangala, M. Tencerova, S.M. Nicoloro, J.C. Yawe, Y. Shen, M.P. Czech, M. Aouadi, Local proliferation of macrophages contributes to obesity-associated adipose tissue inflammation, Cell Metab. 19 (2014) 162–171, http://dx.doi.org/10.1016/j.cmet.2013.11.017. [22] J. Haase, U. Weyer, K. Immig, N. Klöting, M. Blüher, J. Eilers, I. Bechmann, M. Gericke, Local proliferation of macrophages in adipose tissue during obesityinduced inflammation, Diabetologia 57 (2014) 562–571, http://dx.doi.org/10. 1007/s00125-013-3139-y. [23] K. Ohashi, J.L. Parker, N. Ouchi, A. Higuchi, J.A. Vita, N. Gokce, A.A. Pedersen, C. Kalthoff, S. Tullin, A. Sams, R. Summer, K. Walsh, Adiponectin promotes macrophage polarization toward an anti-inflammatory phenotype, J. Biol. Chem. 285 (2010) 6153–6160, http://dx.doi.org/10.1074/jbc.M109.088708. [24] X. Hui, M. Zhang, P. Gu, K. Li, Y. Gao, D. Wu, Y. Wang, A. Xu, Adipocyte SIRT1 controls systemic insulin sensitivity by modulating macrophages in adipose tissue, EMBO Rep. 18 (2017) 645–657, http://dx.doi.org/10.15252/embr.201643184. [25] A. Chalkiadaki, L. Guarente, High-fat diet triggers inflammation-induced cleavage of SIRT1 in adipose tissue to promote metabolic dysfunction, Cell Metab. 16 (2012) 180–188, http://dx.doi.org/10.1016/j.cmet.2012.07.003. [26] G.S. Hotamisligil, N.S. Shargill, B.M. Spiegelman, Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance, Science 259 (1993) 87–91 http://www.ncbi.nlm.nih.gov/pubmed/7678183 (accessed August 30, 2016). [27] K.T. Uysal, S.M. Wiesbrock, M.W. Marino, G.S. Hotamisligil, Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function, Nature 389 (1997) 610–614, http://dx.doi.org/10.1038/39335. [28] A. Takikawa, A. Mahmood, A. Nawaz, T. Kado, K. Okabe, S. Yamamoto, A. Arif, S. Senda, K. Tsuneyama, M. Ikutani, Y. Watanabe, Y. Igarashi, Y. Nagai, K. Takatsu, K. Koizumi, J. Imura, N. Goda, M. Sasahara, M. Matsumoto, K. Saeki, T. Nakagawa, S. Fujisaka, I. Usui, K. Tobe, HIF-1α in myeloid cells promotes adipose tissue remodeling toward insulin resistance, Diabetes (2016), http://dx.doi.org/10.2337/ db16-0012. [29] G.M. Tannahill, A.M. Curtis, J. Adamik, E.M. Palsson-McDermott, A.F. McGettrick, G. Goel, C. Frezza, N.J. Bernard, B. Kelly, N.H. Foley, L. Zheng, A. Gardet, Z. Tong, S.S. Jany, S.C. Corr, M. Haneklaus, B.E. Caffrey, K. Pierce, S. Walmsley, F.C. Beasley, E. Cummins, V. Nizet, M. Whyte, C.T. Taylor, H. Lin, S.L. Masters, E. Gottlieb, V.P. Kelly, C. Clish, P.E. Auron, R.J. Xavier, L.A.J. O’Neill, Succinate is an inflammatory signal that induces IL-1β through HIF-1α, Nature 496 (2013) 238–242, http://dx.doi.org/10.1038/nature11986. [30] E.L. Mills, B. Kelly, A. Logan, A.S.H. Costa, M. Varma, C.E. Bryant, P. Tourlomousis, J.H.M. Däbritz, E. Gottlieb, I. Latorre, S.C. Corr, G. McManus, D. Ryan, H.T. Jacobs, M. Szibor, R.J. Xavier, T. Braun, C. Frezza, M.P. Murphy, L.A. O’Neill, Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages, Cell 167 (2016), http://dx.doi.org/10.1016/j.cell.2016. 08.064 457–470.e13. [31] V. Saraswathi, A.H. Hasty, The role of lipolysis in mediating the proinflammatory effects of very low density lipoproteins in mouse peritoneal macrophages, J. Lipid Res. 47 (2006) 1406–1415, http://dx.doi.org/10.1194/jlr.M600159-JLR200. [32] E.K. Anderson, A.A. Hill, A.H. Hasty, Stearic acid accumulation in macrophages induces toll-like receptor 4/2-independent inflammation leading to endoplasmic reticulum stress-mediated apoptosis, Arterioscler. Thromb. Vasc. Biol. 32 (2012) 1687–1695, http://dx.doi.org/10.1161/ATVBAHA.112.250142. [33] H. Shi, M.V. Kokoeva, K. Inouye, I. Tzameli, H. Yin, J.S. Flier, TLR4 links innate immunity and fatty acid – induced insulin resistance, J. Clin. Invest. 116 (2006) 3015–3025, http://dx.doi.org/10.1172/JCI28898.TLRs. [34] B. Shan, X. Wang, Y. Wu, C. Xu, Z. Xia, J. Dai, M. Shao, F. Zhao, S. He, L. Yang, M. Zhang, F. Nan, J. Li, J. Liu, J. Liu, W. Jia, Y. Qiu, B. Song, J.-D.J. Han, L. Rui, S.Z. Duan, Y. Liu, The metabolic ER stress sensor IRE1α suppresses alternative activation of macrophages and impairs energy expenditure in obesity, Nat. Immunol. (2017), http://dx.doi.org/10.1038/ni.3709. [35] G. Cildir, S.C. Akincilar, V. Tergaonkar, Chronic adipose tissue inflammation: all immune cells on the stage, Trends Mol. Med. 19 (2013) 487–500, http://dx.doi.org/ 10.1016/j.molmed.2013.05.001. [36] D. Wu, A.B. Molofsky, H.-E. Liang, R.R. Ricardo-Gonzalez, H.A. Jouihan, J.K. Bando, A. Chawla, R.M. Locksley, Eosinophils sustain adipose alternative activated macrophages associated with glucose homeostasis, Science 332 (2011) 243–247. [37] J. Deiuliis, Z. Shah, N. Shah, B. Needleman, D. Mikami, V. Narula, K. Perry, J. Hazey, T. Kampfrath, M. Kollengode, Q. Sun, A.R. Satoskar, C. Lumeng, S. Moffatt-Bruce, S. Rajagopalan, Visceral adipose inflammation in obesity is associated with critical alterations in tregulatory cell numbers, PLoS One 6 (2011), http://dx.doi.org/10.1371/journal.pone.0016376. [38] M. Feuerer, L. Herrero, D. Cipolletta, A. Naaz, J. Wong, A. Nayer, J. Lee, A.B. Goldfine, C. Benoist, S. Shoelson, D. Mathis, Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters, Nat. Med. 15 (2009) 930–939, http://dx.doi.org/10.1038/nm.2002. [39] L. Lynch, M. Nowak, B. Varghese, J. Clark, A.E. Hogan, V. Toxavidis, S.P. Balk, D. O’Shea, C. O’Farrelly, M.A. Exley, Adipose tissue invariant NKT cells protect against diet-induced obesity and metabolic disorder through regulatory cytokine production, Immunity 37 (2012) 574–587, http://dx.doi.org/10.1016/j.immuni.
References [1] N. Ouchi, J.L. Parker, J.J. Lugus, K. Walsh, Adipokines in inflammation and metabolic disease, Nat. Rev. Immunol. 11 (2011) 85–97, http://dx.doi.org/10.1038/ nri2921. [2] S.P. Weisberg, D. McCann, M. Desai, M. Rosenbaum, R.L. Leibel, A.W. Ferrante, Obesity is associated with macrophage accumulation in adipose tissue, J. Clin. Invest. 112 (2003) 1796–1808, http://dx.doi.org/10.1172/JCI200319246. [3] C.N. Lumeng, J.L. Bodzin, A.R. Saltiel, Obesity induces a phenotypic switch in adipose tissue macrophage polarization, J. Clin. Invest. 117 (2007) 175–184, http://dx.doi.org/10.1172/JCI29881. [4] C.N. Lumeng, S.M. DeYoung, J.L. Bodzin, A.R. Saltiel, Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity, Diabetes 56 (2007) 16–23, http://dx.doi.org/10.2337/db06-1076. [5] C.N. Lumeng, J.B. Delproposto, D.J. Westcott, A.R. Saltiel, Phenotypic switching of adipose tissue macrophages with obesity is generated by spatiotemporal differences in macrophage subtypes, Diabetes 57 (2008) 3239–3246, http://dx.doi.org/10. 2337/db08-0872. [6] S. Cinti, G. Mitchell, G. Barbatelli, I. Murano, E. Ceresi, E. Faloia, S. Wang, M. Fortier, A.S. Greenberg, M.S. Obin, Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans, J. Lipid Res. 46 (2005) 2347–2355, http://dx.doi.org/10.1194/jlr.M500294-JLR200. [7] I. Murano, G. Barbatelli, V. Parisani, C. Latini, G. Muzzonigro, M. Castellucci, S. Cinti, Dead adipocytes, detected as crown-like structures, are prevalent in visceral fat depots of genetically obese mice, J. Lipid Res. 49 (2008) 1562–1568, http:// dx.doi.org/10.1194/jlr.M800019-JLR200. [8] A.S. Haka, V.C.V.C. Barbosa-Lorenzi, H.J. Lee, D.J. Falcone, C.A. Hudis, A.J. Dannenberg, F.R. Maxfield, Exocytosis of macrophage lysosomes leads to digestion of apoptotic adipocytes and foam cell formation, J. Lipid Res. 57 (2016) 980–992, http://dx.doi.org/10.1194/jlr.M064089. [9] P. Fischer-Posovszky, Q.A. Wang, I.W. Asterholm, J.M. Rutkowski, P.E. Scherer, Targeted deletion of adipocytes by apoptosis leads to adipose tissue recruitment of alternatively activated M2 macrophages, Endocrinology 152 (2011) 3074–3081, http://dx.doi.org/10.1210/en.2011-1031. [10] A. Kosteli, E. Sugaru, G. Haemmerle, J.F. Martin, J. Lei, R. Zechner, A.W.J. Ferrante, Weight loss and lypolisis promote a dynamic immune response in murine adipose tissue, J. Clin. Invest. 120 (2010) 3466–3479, http://dx.doi.org/10.1172/ JCI42845. [11] H. Shapiro, T. Pecht, R. Shaco-Levy, I. Harman-Boehm, B. Kirshtein, Y. Kuperman, A. Chen, M. Blüher, I. Shai, A. Rudich, Adipose tissue foam cells are present in human obesity, J. Clin. Endocrinol. Metab. 98 (2013) 1173–1181, http://dx.doi. org/10.1210/jc.2012-2745. [12] X. Prieur, C.Y.L. Mok, V.R. Velagapudi, V. Núñez, L. Fuentes, D. Montaner, K. Ishikawa, A. Camacho, N. Barbarroja, S. O’Rahilly, J.K. Sethi, J. Dopazo, M. Orešič, M. Ricote, A. Vidal-Puig, Differential lipid partitioning between adipocytes and tissue macrophages modulates macrophage lipotoxicity and M2/M1 polarization in obese mice, Diabetes 60 (2011) 797–809, http://dx.doi.org/10.2337/ db10-0705. [13] A.R. Johnson, Y. Qin, A.J. Cozzo, A.J. Freemerman, M.J. Huang, L. Zhao, B.P. Sampey, J.J. Milner, M.A. Beck, B. Damania, N. Rashid, J.A. Galanko, D.P. Lee, M.L. Edin, D.C. Zeldin, P.T. Fueger, B. Dietz, A. Stahl, Y. Wu, K.L. Mohlke, L. Makowski, Metabolic reprogramming through fatty acid transport protein 1 (FATP1) regulates macrophage inflammatory potential and adipose inflammation, Mol. Metab. 5 (2016) 506–526, http://dx.doi.org/10.1016/j.molmet.2016.04.005. [14] K.D. Nguyen, Y. Qiu, X. Cui, Y.P.S. Goh, J. Mwangi, T. David, L. Mukundan, F. Brombacher, R.M. Locksley, A. Chawla, Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis, Nature 480 (2011) 104–108, http://dx.doi.org/10.1038/nature10653. [15] K. Fischer, H.H. Ruiz, K. Jhun, B. Finan, D.J. Oberlin, V. van der Heide, A.V. Kalinovich, N. Petrovic, Y. Wolf, C. Clemmensen, A.C. Shin, S. Divanovic, F. Brombacher, E. Glasmacher, S. Keipert, M. Jastroch, J. Nagler, K.-W. Schramm, D. Medrikova, G. Collden, S.C. Woods, S. Herzig, D. Homann, S. Jung, J. Nedergaard, B. Cannon, M.H. Tschöp, T.D. Müller, C. Buettner, Alternatively activated macrophages do not synthesize catecholamines or contribute to adipose tissue adaptive thermogenesis, Nat. Med. (2017), http://dx.doi.org/10.1038/nm. 4316. [16] K.-J. Chung, A. Chatzigeorgiou, M. Economopoulou, R. Garcia-Martin, V.I. Alexaki, I. Mitroulis, M. Nati, J. Gebler, T. Ziemssen, S.E. Goelz, J. Phieler, J.-H. Lim, K.P. Karalis, T. Papayannopoulou, M. Blüher, G. Hajishengallis, T. Chavakis, A selfsustained loop of inflammation-driven inhibition of beige adipogenesis in obesity, Nat. Immunol. (2017), http://dx.doi.org/10.1038/ni.3728. [17] W. Ying, M. Riopel, G. Bandyopadhyay, Y. Dong, A. Birmingham, J.B. Seo, J.M. Ofrecio, J. Wollam, A. Hernandez-Carretero, W. Fu, P. Li, J.M. Olefsky, Adipose tissue macrophage-derived exosomal miRNAs can modulate in vivo and in vitro insulin sensitivity, Cell 171 (2017), http://dx.doi.org/10.1016/j.cell.2017.08. 035 372–378.e12. [18] T. Smallie, G. Ricchetti, N.J. Horwood, M. Feldmann, A.R. Clark, L.M. Williams, IL10 inhibits transcription elongation of the human TNF gene in primary macrophages, J. Exp. Med. 207 (2010) 2081–2088, http://dx.doi.org/10.1084/jem. 20100414.
5
Cellular Immunology xxx (xxxx) xxx–xxx
L. Catrysse, G. van Loo
2012.06.016. [40] Y. Ji, S. Sun, A. Xu, P. Bhargava, L. Yang, K.S.L. Lam, B. Gao, C.H. Lee, S. Kersten, L. Qi, Activation of natural killer T cells promotes M2 macrophage polarization in adipose tissue and improves systemic glucose tolerance via interleukin-4 (IL-4)/ STAT6 protein signaling axis in obesity, J. Biol. Chem. 287 (2012) 13561–13571, http://dx.doi.org/10.1074/jbc.M112.350066. [41] J.Y. Huh, J. Park, J.I. Kim, Y.J. Park, Y.K. Lee, J.B. Kim, Deletion of CD1d in adipocytes aggravates adipose tissue inflammation and insulin resistance in obesity, Diabetes 66 (2017) 835–847, http://dx.doi.org/10.2337/db16-1122. [42] H. Zhang, R. Xue, S. Zhu, S. Fu, Z. Chen, R. Zhou, Z. Tian, L. Bai, M2-specific reduction of CD1d switches NKT cell-mediated immune responses and triggers metaflammation in adipose tissue, Nat. Publ. Gr. (2017), http://dx.doi.org/10. 1038/cmi.2017.11. [43] S. Boulenouar, X. Michelet, D. Duquette, M.B. Brenner, U. Von Andrian, S. Boulenouar, X. Michelet, D. Duquette, D. Alvarez, A.E. Hogan, C. Dold, D.O. Connor, S. Stutte, A. Tavakkoli, D. Winters, M.A. Exley, D.O. Shea, M.B. Brenner, U. Von Andrian, L. Lynch, Adipose type one innate lymphoid cells regulate macrophage homeostasis through targeted article adipose type one innate lymphoid cells regulate macrophage homeostasis through targeted cytotoxicity, Immunity 46 (2017) 273–286, http://dx.doi.org/10.1016/j.immuni.2017.01.008. [44] A.B. Molofsky, J.C. Nussbaum, H.-E. Liang, S.J. Van Dyken, L.E. Cheng, A. Mohapatra, A. Chawla, R.M. Locksley, Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages, J. Exp. Med. 210 (2013) 535–549, http://dx.doi.org/10.1084/jem.20121964. [45] J.R. Brestoff, B.S. Kim, S.A. Saenz, R.R. Stine, L.A. Monticelli, G.F. Sonnenberg, J.J. Thome, D.L. Farber, K. Lutfy, P. Seale, D. Artis, Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity, Nature 519 (2015) 242–246, http://dx.doi.org/10.1038/nature14115. [46] E. Hams, R.M. Locksley, A.N.J. McKenzie, P.G. Fallon, Cutting edge: IL-25 elicits innate lymphoid type 2 and type II NKT cells that regulate obesity in mice, J. Immunol. 191 (2013) 5349–5353, http://dx.doi.org/10.4049/jimmunol.1301176. [47] V. Elgazar-Carmon, A. Rudich, N. Hadad, R. Levy, Neutrophils transiently infiltrate intra-abdominal fat early in the course of high-fat feeding, J. Lipid Res. 49 (2008) 1894–1903, http://dx.doi.org/10.1194/jlr.M800132-JLR200. [48] S. Talukdar, D.Y. Oh, G. Bandyopadhyay, D. Li, J. Xu, J. McNelis, M. Lu, P. Li, Q. Yan, Y. Zhu, J. Ofrecio, M. Lin, M.B. Brenner, J.M. Olefsky, Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase, Nat. Med. 18 (2012) 1407–1412, http://dx.doi.org/10.1038/nm.2885. [49] D.A. Winer, S. Winer, L. Shen, P.P. Wadia, J. Yantha, G. Paltser, H. Tsui, P. Wu, M.G. Davidson, M.N. Alonso, H.X. Leong, A. Glassford, M. Caimol, J.A. Kenkel, T.F. Tedder, T. McLaughlin, D.B. Miklos, H.-M. Dosch, E.G. Engleman, B cells
[50]
[51]
[52]
[53]
[54]
[55]
[56]
[57]
[58]
6
promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies, Nat. Med. 17 (2011) 610–617, http://dx.doi.org/10.1038/ nm.2353. S. Nishimura, I. Manabe, M. Nagasaki, K. Eto, H. Yamashita, M. Ohsugi, M. Otsu, K. Hara, K. Ueki, S. Sugiura, K. Yoshimura, T. Kadowaki, R. Nagai, CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity, Nat. Med. 15 (2009) 914–920, http://dx.doi.org/10.1038/nm.1964. V.Z. Rocha, E.J. Folco, G. Sukhova, K. Shimizu, I. Gotsman, A.H. Vernon, P. Libby, Interferon-γ, a Th1 cytokine, regulates fat inflammation: a role for adaptive immunity in obesity, Circ. Res. 103 (2008) 467–476, http://dx.doi.org/10.1161/ CIRCRESAHA.108.177105. L. Pacifico, L. Di Renzo, C. Anania, J.F. Osborn, F. Ippoliti, E. Schiavo, C. Chiesa, Increased T-helper interferon-gamma-secreting cells in obese children, Eur. J. Endocrinol. 154 (2006) 691–697, http://dx.doi.org/10.1530/eje.1.02138. B.-C. Lee, M.-S. Kim, M. Pae, Y. Yamamoto, D. Eberlé, T. Shimada, N. Kamei, H.S. Park, S. Sasorith, J.R. Woo, J. You, W. Mosher, H.J.M. Brady, S.E. Shoelson, J. Lee, Adipose natural killer cells regulate adipose tissue macrophages to promote insulin resistance in obesity, Cell Metab. (2016) 685–698, http://dx.doi.org/10. 1016/j.cmet.2016.03.002. R.W. O’Rourke, K.A. Meyer, C.K. Neeley, G.D. Gaston, P. Sekhri, M. Szumowski, B. Zamarron, C.N. Lumeng, D.L. Marks, Systemic NK cell ablation attenuates intraabdominal adipose tissue macrophage infiltration in murine obesity, Obesity 22 (2014) 2109–2114, http://dx.doi.org/10.1002/oby.20823. F.M. Wensveen, V. Jelenčić, S. Valentić, M. Šestan, T.T. Wensveen, S. Theurich, A. Glasner, D. Mendrila, D. Štimac, F.T. Wunderlich, J.C. Brüning, O. Mandelboim, B. Polić, NK cells link obesity-induced adipose stress to inflammation and insulin resistance, Nat. Immunol. 16 (2015) 376–385, http://dx.doi.org/10.1038/ni.3120. M.J. Kraakman, A.J. Murphy, K. Jandeleit-Dahm, H.L. Kammoun, Macrophage polarization in obesity and type 2 diabetes: weighing down our understanding of macrophage function? Front. Immunol. 5 (2014), http://dx.doi.org/10.3389/ fimmu.2014.00470. X. Xu, A. Grijalva, A. Skowronski, M. van Eijk, M.J. Serlie, A.W. Ferrante, Obesity activates a program of lysosomal-dependent lipid metabolism in adipose tissue macrophages independently of classic activation, Cell Metab. 18 (2013) 816–830, http://dx.doi.org/10.1016/j.cmet.2013.11.001. M. Kratz, B.R. Coats, K.B. Hisert, D. Hagman, V. Mutskov, E. Peris, K.Q. Schoenfelt, J.N. Kuzma, I. Larson, P.S. Billing, R.W. Landerholm, M. Crouthamel, D. Gozal, S. Hwang, P.K. Singh, L. Becker, Metabolic dysfunction drives a mechanistically distinct proinflammatory phenotype in adipose tissue macrophages, Cell Metab. 20 (2014) 614–625, http://dx.doi.org/10.1016/j.cmet.2014.08.010.
Contents lists available at ScienceDirect
Cellular Immunology journal homepage: www.elsevier.com/locate/ycimm
Research paper
Adipose tissue macrophages and their polarization in health and obesity Leen Catryssea,b, Geert van Looa,b, a b
⁎
VIB Center for Inflammation Research, B-9052 Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, B-9052 Ghent, Belgium
A R T I C LE I N FO
A B S T R A C T
Keywords: Obesity Adipose tissue macrophages Macrophage polarization
Adipose tissue is a special tissue environment due to its high lipid content. Adipose tissue macrophages (ATMs) help maintain adipose tissue homeostasis in steady state by clearing dead adipocytes. However, adipose tissue changes drastically during obesity, resulting in a state of chronic low grade inflammation and a shift in the adipose immune landscape. In this review we will discuss how these changes influence the polarization of ATMs.
1. Introduction People gain weight when their energy intake exceeds the energy demand of their body. As a consequence, the excess energy is stored in the adipose tissue. However, adipose tissue is not just a neutral storage place for lipids, it is considered to be an endocrine organ that can secrete a wide range of hormones and adipokines that regulate systemic metabolism [1]. Adipose tissue is mostly composed of adipocytes, but it also contains resident immune cells that help maintain organ homeostasis. From these, adipose tissue macrophages (ATMs) are the most abundant leukocyte population, constituting around 5% of the adipose tissue in lean state, which increases dramatically in conditions of obesity both in humans and in mice (up to 50% of adipose tissue) [2]. Obesity is associated with a low grade inflammatory state, characterized by elevated serum levels of inflammatory mediators such as TNF and IL-1β, and the presence of circulating bacterial lipopolysaccharide (LPS), which induce inflammation in different metabolic tissues. In visceral fat, this is accompanied by a dramatic shift in the immune landscape with more pro-inflammatory immune cells inducing inflammatory responses. This shift is most apparent in ATMs, as these cells not only greatly expand in number, but also shift their phenotype from so-called alternatively activated ‘M2’ macrophages to classically activated ‘M1’ macrophages [3]. In lean conditions, ATMs express classical ‘M2’ genes such as IL-10, Mrc2, Ym1/Chi3l3 and Mgl1/2, while in obese fat ATMs mainly express pro-inflammatory genes such as IL-6 and Nos2, reminiscent of classical ‘M1’ macrophages [4]. In addition, both ATM populations can be distinguished based on the expression of surface markers, where in lean fat tissue the majority of ATMs express CD206, while in obese conditions M1-like macrophages accumulate and upregulate CD11c (Table 1). This distinction between both types of macrophages is also reflected in their location, as CD206+ M2
⁎
macrophages mostly reside interstitially in between the adipocytes, while CD11c+ M1 macrophages are mainly found in Crown Like Structures (CLS) [5]. According to the current hypothesis, this phenotypic switch of ATMs is believed to be crucial to promote the pro-inflammatory environment in obese adipose tissue, affecting insulin sensitivity in peripheral organs [6,7]. 2. ATMs regulate adipose tissue homeostasis in steady lean state Adipose tissue macrophages are the tissue resident macrophages of adipose tissue and they are important to help maintain tissue homeostasis in steady state. Their main function is to engulf dead adipocytes to help in the cellular turnover of these cells. In the lean state, ATMs occasionally form a CLS around a dying adipocyte, however, since adipocytes are much larger compared to ATMs, they are not able to engulf the entire adipocyte. To solve this, the ATMs form an extracellular acidic compartment around the dead adipocyte, by the release of their lysosomal enzymes through exocytosis, as shown in humans and in mice. As a result, the lysosomal enzymes liberate the free fatty acids (FFA), which are then taken up by the macrophages to be processed [8]. Interestingly, when adipocyte apoptosis is induced in mice, mostly alternatively activated CD206+ M2 macrophages are recruited [9]. This indicates that adipocyte death alone is not enough to drive the switch to more inflammatory M1 macrophages suggesting that other factors, including live adipokine-secreting adipocytes are necessary to sustain the inflammation in adipose tissue. Moreover, the process of CLS formation and the clean removal of dead adipocytes is considered to be beneficial for tissue homeostasis, but in obese conditions this system is clearly out of balance. Besides their role in the removal of dead adipocytes, ATMs also buffer part of the lipid pool present in the adipose tissue. When lipolysis
Corresponding author at: Center for Inflammation Research, VIB and Ghent University, Technologiepark 927, B-9052 Ghent, Belgium. E-mail address: [email protected] (G. van Loo).
https://doi.org/10.1016/j.cellimm.2018.03.001 Received 15 October 2017; Received in revised form 14 February 2018; Accepted 1 March 2018 0008-8749/ © 2018 Elsevier Inc. All rights reserved.
Please cite this article as: Catrysse, L., Cellular Immunology (2018), https://doi.org/10.1016/j.cellimm.2018.03.001
Cellular Immunology xxx (xxxx) xxx–xxx
L. Catrysse, G. van Loo
with the accumulation of lipid species in mouse ATMs, which coincides with the induction of gene-expression networks associated with lipid uptake, storage, and metabolism [12]. Interestingly, the lipid trafficking protein fatty acid transport protein 1 (FATP1) in mouse macrophages was shown to play a critical role in suppressing macrophage activation and adipocyte inflammation through modulation of glucose metabolism and oxidative stress, identifying FATP1 as a regulator of immunometabolism [13]. Further research on lipid buffering and macrophage polarization in the context of obesity would be important to fully understand the metabolic changes in adipose macrophages and its resulting consequences. Recently, a lot of research has been done on the role of immune cells and the process of non-shivering thermogenesis or browning. In the current hypothesis it is believed that thermogenesis is activated by the joint interaction of eosinophils and type 2 Innate Lymphoid Cells (ILC2), leading to the alternative activation of ATMs, which start secreting catecholamines to induce the expression of thermogenic genes in brown adipose tissue (BAT) and lipolysis in white adipose tissue (WAT) of mice [14]. Depletion of alternatively activated ATMs impairs the thermogenic response to cold, while IL4 induces catecholamine synthesis, triglyceride lipolysis and thermogenic gene expression in adipocytes [14]. However, this hypothesis has recently been challenged, since the deletion of tyrosine hydroxylase, a key enzyme in the catecholamine synthesis pathway, in hematopoietic cells was shown to have no effect on thermogenesis upon cold exposure in mice [15]. Interestingly, another recent study showed that M1 ATMs express α4 integrin, which interacts with VCAM-1 on adipocytes of the
Table 1 Markers for adipose tissue macrophages.
Mouse
Human
ATMs
M1 ATMs
M2 ATMs
CD45+ CD11b+ F4/80+
CD11c+
CD206+ Optional: CD301+ Arginase 1+
Optional: CD64+ Siglec F− Ly6G− Ly6C− CD68+ CD14+
Optional: MHCII+ iNOS+
CD11c+
CD163+ Optional: CD204+ CD206+
is induced due to weight loss or starvation, ATMs get recruited to the adipose tissue, adopt an anti-inflammatory phenotype and take up the released lipids [10]. Hence, when macrophages are depleted from the abdomen and lipolysis is induced in mice, FFA levels in the serum rise extensively. These findings demonstrate that local lipid fluxes regulate ATM recruitment to buffer local increases in lipid concentration [10]. In obese conditions, the macrophages in the CLS also contain multiple lipid droplets and resemble foam cells, both in human and murine adipose tissue, however, here the lipid buffering capacity is insufficient to cope with the nutrient overload [6,11]. M1 polarization is associated
Fig. 1. The adipocyte niche influences macrophage polarization. In lean adipose tissue the adipocytes are well vascularized, insulin sensitive and healthy. Adipocytes produce factors including adiponectin to promote the alternative activation of CD206+ ATMs (green), and as a response these ATMs produce beneficial cytokines including IL-10. CD206+ ATMs present lipid antigens through their CD1d receptor to NKT cells, which stimulates their proliferation and activation. In return, NKT cells stimulate CD206+ polarization by producing IL-4 and IL10. Regulatory T cells also produce the beneficial IL-10 and in vitro assays suggest that CD11c+ ATMs can inhibit Treg differentiation, leading to their reduction in obesity. In lean adipose tissue, ILC1s have recently been shown to kill damaged CD206+ ATMs. Eosinophils and ILC2s work together to stimulate M2 polarization, through the production of IL-4 and IL-5/IL-13, respectively. In obese adipose tissue, the immune landscape changes drastically with more pro-inflammatory immune cells. Also, adipocytes are hypoxic, insulin resistant and stressed. Pro-inflammatory CD11c+ ATMs (red) accumulate, due to the increased levels of FFA, pro-inflammatory cytokines, hypoxia and ER stress. These ATMs are typically found in crown like structures (CLS) around a dying adipocyte (grey). In addition, neutrophils accumulate and stimulate CD11c+ M1 polarization through the secretion of elastase. Furthermore, B cells secrete IgGs, especially around CLS, which stimulates pro-inflammatory ATM polarization, together with CD8+ T cells and IFN-γ producing Th1 T cells. Also NK cells accumulate, producing more pro-inflammatory mediators including TNF and MCP1. CD11c+ ATMs have also been found to stimulate NK cell accumulation and proliferation, through, for example, the production of IL-15. ILC1/2 (Innate Lymphoid Cells 1/2), NKT cells (Natural Killer T cells), NK cells (Natural Killer cells), FFA (Free Fatty Acids), IRE1α (Inositol-requiring enzyme 1), HIF-1α (Hypoxia-inducible factor-1).
2
Cellular Immunology xxx (xxxx) xxx–xxx
L. Catrysse, G. van Loo
macrophages and induce a pro-inflammatory environment [26,27]. Because the adipose tissue has to expand so rapidly during obesity, the vasculature cannot follow, causing hypoxia-mediated dysfunction of the adipose tissue. However, also ATMs suffer from this hypoxia. Absence of HIF-1α, a master regulator of hypoxic responses, in myeloid cells was shown to protect mice from HFD-induced inflammation, CLS formation, poor adipose tissue vascularization and systemic insulin resistance. Moreover, the HIF-1α-deficient M1 macrophages inhibit the expression of angiogenic factors in adipocytes [28]. These data identify macrophage HIF-1α as a strong promotor of adipose tissue inflammation and adipose tissue remodeling inducing insulin resistance. HIF-1α was also shown to specifically regulate gene expression of IL-1β and other HIF-1α-dependent inflammatory genes in mice [29,30]. ATM polarization is also affected by the lipid load which is much higher in obese conditions, as mentioned above. Indeed, exposure of mouse macrophages to Very Low-Density Lipoproteins (VLDLs) and short chain fatty acids induces the secretion of typical pro-inflammatory M1 cytokines [31,32]. In addition, FFA, whose circulating levels are increased in obesity, can activate TLR4 signaling in murine ATMs, indicative of M1 polarization [33]. Finally, also endoplasmic reticulum (ER) stress enhances macrophage activation. Inositol-requiring enzyme 1α (IRE1α) was recently shown to act as a critical switch governing M1-M2 macrophage polarization [34]. Mice with myeloid-specific IRE1α deficiency are completely protected from HFD-induced obesity and insulin resistance, due to a reduction in fat mass, increased energy expenditure and enhanced browning [34]. In agreement, deficiency of IRE1α was shown to promote M2 polarization of macrophages, and transcriptome analysis revealed that IRE1α downregulates IRF4 and KLF4 expression, both key regulators of M2 polarization [34]. Interestingly, the ATM polarization is not affected in the lean state, indicating that there are obesogenic factors including FFA and LPS that can activate IRE1α in macrophages.
subcutaneous white adipose tissue in both the human and mouse system, leading to the downregulation of the thermogenic program [16]. Genetic or pharmacological inactivation of α4 integrin does not affect adiposity, but improves the thermogenic capacity and insulin sensitivity of adipocytes due to a reduction in M1 macrophage infiltration and CLS formation. In obesity, M1 macrophages even stimulate adipocytes to upregulate VCAM1, suggesting a self-sustained inflammatory loop to impair beige adipogenesis and to aggravate insulin resistance [16]. Finally, a new mechanism has been proposed whereby ATMs regulate insulin action and systemic insulin sensitivity by secreting microRNA containing exosomes into the circulation [17]. MiRNA-155 is one of the miRNAs overexpressed in obese ATM exosomes, and was shown to inhibit insulin signaling through a mechanism most likely related to a direct suppression of its target gene PPARγ [17]. However, most probably, also other miRNAs within these exosomes may have functional roles. 3. What drives the phenotypic switch between M1 and M2 during obesity ? ATMs are important to maintain adipose tissue homeostasis, however, during obesity ATMs switch their homeostatic phenotype to a proinflammatory phenotype that drives the development of insulin resistance (Fig. 1). The anti-inflammatory M2 ATMs preserve adipocyte insulin sensitivity by the production of IL-10, which has been shown to directly counteract the negative effects of TNF [3,18]. On the other hand, the pro-inflammatory M1 ATMs found in obese adipose tissue produce inflammatory cytokines including TNF, contributing to the development of insulin resistance [19]. When CD11c+ ATMs are depleted using a mouse diphtheria toxin model, insulin sensitivity is restored, inflammatory cytokines are suppressed, while IL-10 expression is increased [20]. An important question here is what drives this macrophage polarization switch from M2 to M1 ATMs.
3.2. The interplay with other immune cells Next to its effect on ATMs, it is now clear that obesity affects all immune cell types in adipose tissue [35]. Many immune cell types, including neutrophils, B cells, CD8 T cells, and Natural Killer cells accumulate in adipose tissue upon obesity, while eosinophils, Regulatory T cells, Natural Killer T cells and Type 2 Innate Lymphoid Cells decrease in numbers in obese conditions (Fig. 1).
3.1. Obese adipose tissue: a specific niche Adipose tissue is a special environment, unlike other organs in the body, because of its high fat content. In a lean state, ATMs are adapted to this specific situation. However, due to a chronic nutrient overload in conditions of obesity, adipocytes need to store excessive amounts of fat in a short time, causing a lot of adipocyte stress and eventually adipocyte death, explaining the increased number of CLS in obese adipose tissue. What type of adipocyte cell death occurs during obesity and how this influences ATM polarization is still unclear. Electron microscopy analysis of both human and mouse obese adipose tissue revealed ruptured adipocyte membranes and the presence of cellular debris, dilated endoplasmatic reticulum and small cytoplasmic lipid droplets, indicative of necrosis [6]. Interestingly, in both humans and mice, increased numbers of proliferating ATMs have been found preferentially in CLS regions, but independent of the activation state, suggesting that dying adipocytes secrete ATM proliferating factors [21,22]. However, additional studies using genetic approaches are needed to determine the type of adipocyte death that occurs during obesity, and how this influences ATM proliferation and activation. Adipocytes normally secrete the beneficial adipokine adiponectin, which stimulates M2 ATM polarization. In obesity however, adiponectin secretion is reduced, both in human and mouse models [23]. An important regulator for this could be the SIRTuin deacetylase SIRT1, which modulates the expression and secretion of several adipokines including adiponectin and IL-4 in mouse adipocytes, which in turn alters the recruitment and polarization of ATMs in adipose tissue maintaining insulin sensitivity [24]. Interestingly, SIRT1 undergoes proteolytic degradation in mouse adipose tissue upon prolonged HFD feeding exacerbating insulin resistance [25]. Obese adipocytes also secrete proinflammatory mediators including TNF and MCP1, which attract
3.2.1. Eosinophils The major IL-4 producing source in murine adipose tissue are eosinophils, which, through their production of IL-4 and IL-13, stimulate M2 ATM polarization [36]. In normal lean adipose tissue, the number of eosinophils account for 4–5% of the stromal vascular fraction, however, this decreases upon obesity, affecting the activation state of ATMs [36]. 3.2.2. Regulatory T cells About 10% of the stromal vascular fraction are regulatory T cells (Tregs) [37] which help maintain an anti-inflammatory environment by producing IL-10, thereby regulating insulin sensitivity in both humans and mice. In obese conditions however, Treg numbers are strongly reduced [38]. Although it is not known if Tregs interact with ATMs in vivo, in vitro assays have shown that media from classically activated M1 macrophages is able to inhibit Treg differentiation, while media from alternatively activated M2 macrophages does not [37], suggesting that the phenotypic switch seen in ATMs might contribute to the reduction in Treg cells in obesity. 3.2.3. Natural Killer T cells Natural Killer T (NKT) cells have important immunoregulatory functions also in adipose tissue, where they produce IL-4 and IL-10 and protect against diet-induced obesity in both humans and mice [39]. Their abundance in adipose tissue decreases with increasing adiposity 3
Cellular Immunology xxx (xxxx) xxx–xxx
L. Catrysse, G. van Loo
macrophage infiltration and adipose tissue inflammation [50]. Conversely, adoptive transfer of CD8+ T cells into CD8-deficient obese mice induces M1 macrophage infiltration and adipose tissue inflammation [50]. These data demonstrate that CD8+ T cells contribute to the propagation of adipose tissue inflammation and the development of insulin resistance in mice. In addition, increased numbers of IFN-γ producing Th1 cells have been found in both obese humans and mice, and in vitro studies showed that T cells from obese adipose tissue produce more IFN-γ, a potent stimulus to drive M1 polarization [51,52].
and insulin resistance. Specific activation of NKT cells via their lipid ligand α-galactosylceramide enhances anti-inflammatory gene expression in the adipose tissue and improves glucose homeostasis in an IL-4/ STAT6 dependent way [40]. Loss of CD1d in murine adipocytes reduces the number of NKT cells in the adipose tissue, resulting in an accumulation of M1 ATMs and a worsened insulin resistance [41]. NKT cell activation by M2 ATMs, however, stimulates Th2 responses and M2 polarization, and inhibits insulin resistance in mice [42]. Based on this, a model is proposed which suggests that an M2 ATM-specific reduction of CD1d is an initiating event that switches NKT cell-mediated immune responses and disrupts the immune balance in visceral adipose tissues in obese mice [42].
3.2.9. Natural Killer cells Natural Killer (NK) cells accumulate in adipose tissue and promote insulin resistance in obesity in mice. NK cell deletion reduces pro-inflammatory M1 ATM numbers, while NK cell expansion shows the opposite [53–55]. Interestingly, adipose NK cells control ATMs potentially by producing pro-inflammatory mediators, including TNF and MCP1. Also, obesity not only increases NK numbers, but it also makes them produce more TNF, most likely because obese ATMs produce more NK chemoattractants such as IL-15, which promotes NK cell activation and proliferation [53]. Importantly, gain or loss of NK cells has no effect in lean mice, indicating that the obesogenic environment is crucial for their function.
3.2.4. Type 1 Innate Lymphoid Cells 1 Type 1 Innate Lymphoid Cells (ILC1s) are enriched in human and mouse adipose tissue where their number rises in a short time period right after the onset of HFD feeding [43]. Interestingly, ILC1s are found in the proximity of stressed ATMs, marked by the expression of the stress ligand Rae-1, and are able to kill ATMs ex vivo, particularly M2 ATMs [43]. Depletion of adipose tissue ILC1s in lean mice results in alterations in the ratio of inflammatory to anti-inflammatory ATMs, and adoptive transfer of lean ILC1s exacerbated metabolic disease [43]. However, the ATM killing capacity of ILC1s is lost in conditions of obesity, indicating a role for ILC1s in regulating ATM homeostasis, which seems to be disturbed in obesity.
4. The M1/M2 paradigm: an oversimplification Obesity is generally characterized and described by the presence of an increased population of pro-inflammatory M1 ATMs that express CD11c, while lean adipose tissue by the presence of anti-inflammatory M2 ATMs that express CD206 and MGL1/2. However, this M1/M2 classification is an oversimplification, and macrophages display a more dynamic and varied spectrum of activation states in between the two extreme M1 and M2 classes [56]. The M1/M2 classification is entirely based on a very biased approach where only a specific set of pro- and anti-inflammatory genes is considered and is mostly based on studies done in mice. An unbiased approach such as a full transcriptome analysis gives a more objective view on the identity and function of ATMs and how these change during the course of obesity. Using such an unbiased transcriptome analysis on CD11c+ and CD11c− ATMs in different models of obesity, Xu et al. could not identify a prototype M1 signature associated with a classical inflammatory phenotype but, instead, a signature of lysosomal-dependent lipid metabolism [57]. The prototype expression of genes associated with classically activated, M1polarized macrophages or alternatively activated M2-polarized macrophages was not different between ATMs in lean and obese mice, arguing against a simple binary switch in ATMs in obesity [57]. The changes in the inflammatory profile of the adipose tissue in obesity rather reflect quantitative changes in the number of macrophages and other immune cell populations infiltrating the adipose tissue. Using a proteomics approach, Kratz et al. could also not identify the typical markers of classical M1 ATM activation in macrophages from obese humans, but again identified proteins that promote lipid metabolism [58]. These ‘omics’ approaches and new technologies including single cell RNA sequencing will be very helpful to identify and better characterize different ATM populations and their impact on metabolic changes in the adipose tissue.
3.2.5. Type 2 Innate Lymphoid Cells ILC2s promote the accumulation of eosinophils and M2 ATMs by providing a major source of IL-5 and IL-13 to murine adipose tissue [44]. Depletion of ILC2s in mice greatly reduces the number of eosinophils and M2 ATMs in adipose tissue [44]. ILC2s have also been shown to regulate thermogenesis and browning in mice, by producing methionine-enkephalin peptides [45]. In obesity, ILC2 levels decrease, hence their strong anti-inflammatory effects are lost [44,45]. Indeed, depletion of ILC2s in obese mice leads to exacerbation of weight gain and glucose intolerance, while transfer of ILC2 in obese mice promotes weight loss [46]. 3.2.6. Neutrophils Neutrophils are recruited to murine adipose tissue in conditions of obesity [47]. Neutrophil recruitment has a negative impact on the development of insulin resistance, mainly because of the proteases they secrete, one of which is neutrophil elastase. Deletion of neutrophil elastase in high-fat-diet–induced obese mice reduces adipose tissue inflammation and lowers adipose tissue neutrophil and macrophage content. These changes are accompanied by improved glucose tolerance and increased insulin sensitivity [48]. Since neutrophil elastase is able to induce M1 macrophage polarization in vitro, recruitment of neutrophils to adipose tissue is considered to be an important determinant in the polarization switch seen in ATMs. 3.2.7. B Cells B cells contribute to the development of insulin resistance, and mice lacking B cells have improved glucose homeostasis despite weight gain [49]. B cells promote T cell activation and pro-inflammatory cytokine production, which potentiate M1 macrophage polarization and insulin resistance. Besides, B cells also produce pathogenic IgG antibodies [49]. Murine crown like structures appear to be surrounded by tissue fluid enriched for IgM and IgG, and the Fc portion of IgG is able to activate ATMs to produce more TNF [49].
Conflict of interest The authors declare no conflict of interest. Acknowledgements
3.2.8. T cells Infiltration of CD8+ effector T cells is an early event during the development of obesity in mice and even precedes macrophage accumulation [50]. Deletion of CD8+ T cells in obese mice does not affect body weight, but ameliorates insulin resistance and lowers M1
L. Catrysse was supported as a PhD fellow by the “Instituut voor Innovatie door Wetenschap en Technologie” (IWT) and by a research grant from “Kom op tegen Kanker”. Research in the van Loo lab is supported by grants from VIB, the Fund for Scientific Research Flanders 4
Cellular Immunology xxx (xxxx) xxx–xxx
L. Catrysse, G. van Loo
(FWO), the Foundation against Cancer, the Queen Elisabeth Medical Foundation, the Charcot Foundation, and the Concerted Research Actions (GOA) of the Ghent University.
[19] O. Osborn, J.M. Olefsky, The cellular and signaling networks linking the immune system and metabolism in disease, Nat. Med. 18 (2012) 363–374, http://dx.doi. org/10.1038/nm.2627. [20] D. Patsouris, P.P. Li, D. Thapar, J. Chapman, J.M. Olefsky, J.G. Neels, Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals, Cell Metab. 8 (2008) 301–309, http://dx.doi.org/10.1016/j.cmet.2008.08. 015. [21] S.U. Amano, J.L. Cohen, P. Vangala, M. Tencerova, S.M. Nicoloro, J.C. Yawe, Y. Shen, M.P. Czech, M. Aouadi, Local proliferation of macrophages contributes to obesity-associated adipose tissue inflammation, Cell Metab. 19 (2014) 162–171, http://dx.doi.org/10.1016/j.cmet.2013.11.017. [22] J. Haase, U. Weyer, K. Immig, N. Klöting, M. Blüher, J. Eilers, I. Bechmann, M. Gericke, Local proliferation of macrophages in adipose tissue during obesityinduced inflammation, Diabetologia 57 (2014) 562–571, http://dx.doi.org/10. 1007/s00125-013-3139-y. [23] K. Ohashi, J.L. Parker, N. Ouchi, A. Higuchi, J.A. Vita, N. Gokce, A.A. Pedersen, C. Kalthoff, S. Tullin, A. Sams, R. Summer, K. Walsh, Adiponectin promotes macrophage polarization toward an anti-inflammatory phenotype, J. Biol. Chem. 285 (2010) 6153–6160, http://dx.doi.org/10.1074/jbc.M109.088708. [24] X. Hui, M. Zhang, P. Gu, K. Li, Y. Gao, D. Wu, Y. Wang, A. Xu, Adipocyte SIRT1 controls systemic insulin sensitivity by modulating macrophages in adipose tissue, EMBO Rep. 18 (2017) 645–657, http://dx.doi.org/10.15252/embr.201643184. [25] A. Chalkiadaki, L. Guarente, High-fat diet triggers inflammation-induced cleavage of SIRT1 in adipose tissue to promote metabolic dysfunction, Cell Metab. 16 (2012) 180–188, http://dx.doi.org/10.1016/j.cmet.2012.07.003. [26] G.S. Hotamisligil, N.S. Shargill, B.M. Spiegelman, Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance, Science 259 (1993) 87–91 http://www.ncbi.nlm.nih.gov/pubmed/7678183 (accessed August 30, 2016). [27] K.T. Uysal, S.M. Wiesbrock, M.W. Marino, G.S. Hotamisligil, Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function, Nature 389 (1997) 610–614, http://dx.doi.org/10.1038/39335. [28] A. Takikawa, A. Mahmood, A. Nawaz, T. Kado, K. Okabe, S. Yamamoto, A. Arif, S. Senda, K. Tsuneyama, M. Ikutani, Y. Watanabe, Y. Igarashi, Y. Nagai, K. Takatsu, K. Koizumi, J. Imura, N. Goda, M. Sasahara, M. Matsumoto, K. Saeki, T. Nakagawa, S. Fujisaka, I. Usui, K. Tobe, HIF-1α in myeloid cells promotes adipose tissue remodeling toward insulin resistance, Diabetes (2016), http://dx.doi.org/10.2337/ db16-0012. [29] G.M. Tannahill, A.M. Curtis, J. Adamik, E.M. Palsson-McDermott, A.F. McGettrick, G. Goel, C. Frezza, N.J. Bernard, B. Kelly, N.H. Foley, L. Zheng, A. Gardet, Z. Tong, S.S. Jany, S.C. Corr, M. Haneklaus, B.E. Caffrey, K. Pierce, S. Walmsley, F.C. Beasley, E. Cummins, V. Nizet, M. Whyte, C.T. Taylor, H. Lin, S.L. Masters, E. Gottlieb, V.P. Kelly, C. Clish, P.E. Auron, R.J. Xavier, L.A.J. O’Neill, Succinate is an inflammatory signal that induces IL-1β through HIF-1α, Nature 496 (2013) 238–242, http://dx.doi.org/10.1038/nature11986. [30] E.L. Mills, B. Kelly, A. Logan, A.S.H. Costa, M. Varma, C.E. Bryant, P. Tourlomousis, J.H.M. Däbritz, E. Gottlieb, I. Latorre, S.C. Corr, G. McManus, D. Ryan, H.T. Jacobs, M. Szibor, R.J. Xavier, T. Braun, C. Frezza, M.P. Murphy, L.A. O’Neill, Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages, Cell 167 (2016), http://dx.doi.org/10.1016/j.cell.2016. 08.064 457–470.e13. [31] V. Saraswathi, A.H. Hasty, The role of lipolysis in mediating the proinflammatory effects of very low density lipoproteins in mouse peritoneal macrophages, J. Lipid Res. 47 (2006) 1406–1415, http://dx.doi.org/10.1194/jlr.M600159-JLR200. [32] E.K. Anderson, A.A. Hill, A.H. Hasty, Stearic acid accumulation in macrophages induces toll-like receptor 4/2-independent inflammation leading to endoplasmic reticulum stress-mediated apoptosis, Arterioscler. Thromb. Vasc. Biol. 32 (2012) 1687–1695, http://dx.doi.org/10.1161/ATVBAHA.112.250142. [33] H. Shi, M.V. Kokoeva, K. Inouye, I. Tzameli, H. Yin, J.S. Flier, TLR4 links innate immunity and fatty acid – induced insulin resistance, J. Clin. Invest. 116 (2006) 3015–3025, http://dx.doi.org/10.1172/JCI28898.TLRs. [34] B. Shan, X. Wang, Y. Wu, C. Xu, Z. Xia, J. Dai, M. Shao, F. Zhao, S. He, L. Yang, M. Zhang, F. Nan, J. Li, J. Liu, J. Liu, W. Jia, Y. Qiu, B. Song, J.-D.J. Han, L. Rui, S.Z. Duan, Y. Liu, The metabolic ER stress sensor IRE1α suppresses alternative activation of macrophages and impairs energy expenditure in obesity, Nat. Immunol. (2017), http://dx.doi.org/10.1038/ni.3709. [35] G. Cildir, S.C. Akincilar, V. Tergaonkar, Chronic adipose tissue inflammation: all immune cells on the stage, Trends Mol. Med. 19 (2013) 487–500, http://dx.doi.org/ 10.1016/j.molmed.2013.05.001. [36] D. Wu, A.B. Molofsky, H.-E. Liang, R.R. Ricardo-Gonzalez, H.A. Jouihan, J.K. Bando, A. Chawla, R.M. Locksley, Eosinophils sustain adipose alternative activated macrophages associated with glucose homeostasis, Science 332 (2011) 243–247. [37] J. Deiuliis, Z. Shah, N. Shah, B. Needleman, D. Mikami, V. Narula, K. Perry, J. Hazey, T. Kampfrath, M. Kollengode, Q. Sun, A.R. Satoskar, C. Lumeng, S. Moffatt-Bruce, S. Rajagopalan, Visceral adipose inflammation in obesity is associated with critical alterations in tregulatory cell numbers, PLoS One 6 (2011), http://dx.doi.org/10.1371/journal.pone.0016376. [38] M. Feuerer, L. Herrero, D. Cipolletta, A. Naaz, J. Wong, A. Nayer, J. Lee, A.B. Goldfine, C. Benoist, S. Shoelson, D. Mathis, Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters, Nat. Med. 15 (2009) 930–939, http://dx.doi.org/10.1038/nm.2002. [39] L. Lynch, M. Nowak, B. Varghese, J. Clark, A.E. Hogan, V. Toxavidis, S.P. Balk, D. O’Shea, C. O’Farrelly, M.A. Exley, Adipose tissue invariant NKT cells protect against diet-induced obesity and metabolic disorder through regulatory cytokine production, Immunity 37 (2012) 574–587, http://dx.doi.org/10.1016/j.immuni.
References [1] N. Ouchi, J.L. Parker, J.J. Lugus, K. Walsh, Adipokines in inflammation and metabolic disease, Nat. Rev. Immunol. 11 (2011) 85–97, http://dx.doi.org/10.1038/ nri2921. [2] S.P. Weisberg, D. McCann, M. Desai, M. Rosenbaum, R.L. Leibel, A.W. Ferrante, Obesity is associated with macrophage accumulation in adipose tissue, J. Clin. Invest. 112 (2003) 1796–1808, http://dx.doi.org/10.1172/JCI200319246. [3] C.N. Lumeng, J.L. Bodzin, A.R. Saltiel, Obesity induces a phenotypic switch in adipose tissue macrophage polarization, J. Clin. Invest. 117 (2007) 175–184, http://dx.doi.org/10.1172/JCI29881. [4] C.N. Lumeng, S.M. DeYoung, J.L. Bodzin, A.R. Saltiel, Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity, Diabetes 56 (2007) 16–23, http://dx.doi.org/10.2337/db06-1076. [5] C.N. Lumeng, J.B. Delproposto, D.J. Westcott, A.R. Saltiel, Phenotypic switching of adipose tissue macrophages with obesity is generated by spatiotemporal differences in macrophage subtypes, Diabetes 57 (2008) 3239–3246, http://dx.doi.org/10. 2337/db08-0872. [6] S. Cinti, G. Mitchell, G. Barbatelli, I. Murano, E. Ceresi, E. Faloia, S. Wang, M. Fortier, A.S. Greenberg, M.S. Obin, Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans, J. Lipid Res. 46 (2005) 2347–2355, http://dx.doi.org/10.1194/jlr.M500294-JLR200. [7] I. Murano, G. Barbatelli, V. Parisani, C. Latini, G. Muzzonigro, M. Castellucci, S. Cinti, Dead adipocytes, detected as crown-like structures, are prevalent in visceral fat depots of genetically obese mice, J. Lipid Res. 49 (2008) 1562–1568, http:// dx.doi.org/10.1194/jlr.M800019-JLR200. [8] A.S. Haka, V.C.V.C. Barbosa-Lorenzi, H.J. Lee, D.J. Falcone, C.A. Hudis, A.J. Dannenberg, F.R. Maxfield, Exocytosis of macrophage lysosomes leads to digestion of apoptotic adipocytes and foam cell formation, J. Lipid Res. 57 (2016) 980–992, http://dx.doi.org/10.1194/jlr.M064089. [9] P. Fischer-Posovszky, Q.A. Wang, I.W. Asterholm, J.M. Rutkowski, P.E. Scherer, Targeted deletion of adipocytes by apoptosis leads to adipose tissue recruitment of alternatively activated M2 macrophages, Endocrinology 152 (2011) 3074–3081, http://dx.doi.org/10.1210/en.2011-1031. [10] A. Kosteli, E. Sugaru, G. Haemmerle, J.F. Martin, J. Lei, R. Zechner, A.W.J. Ferrante, Weight loss and lypolisis promote a dynamic immune response in murine adipose tissue, J. Clin. Invest. 120 (2010) 3466–3479, http://dx.doi.org/10.1172/ JCI42845. [11] H. Shapiro, T. Pecht, R. Shaco-Levy, I. Harman-Boehm, B. Kirshtein, Y. Kuperman, A. Chen, M. Blüher, I. Shai, A. Rudich, Adipose tissue foam cells are present in human obesity, J. Clin. Endocrinol. Metab. 98 (2013) 1173–1181, http://dx.doi. org/10.1210/jc.2012-2745. [12] X. Prieur, C.Y.L. Mok, V.R. Velagapudi, V. Núñez, L. Fuentes, D. Montaner, K. Ishikawa, A. Camacho, N. Barbarroja, S. O’Rahilly, J.K. Sethi, J. Dopazo, M. Orešič, M. Ricote, A. Vidal-Puig, Differential lipid partitioning between adipocytes and tissue macrophages modulates macrophage lipotoxicity and M2/M1 polarization in obese mice, Diabetes 60 (2011) 797–809, http://dx.doi.org/10.2337/ db10-0705. [13] A.R. Johnson, Y. Qin, A.J. Cozzo, A.J. Freemerman, M.J. Huang, L. Zhao, B.P. Sampey, J.J. Milner, M.A. Beck, B. Damania, N. Rashid, J.A. Galanko, D.P. Lee, M.L. Edin, D.C. Zeldin, P.T. Fueger, B. Dietz, A. Stahl, Y. Wu, K.L. Mohlke, L. Makowski, Metabolic reprogramming through fatty acid transport protein 1 (FATP1) regulates macrophage inflammatory potential and adipose inflammation, Mol. Metab. 5 (2016) 506–526, http://dx.doi.org/10.1016/j.molmet.2016.04.005. [14] K.D. Nguyen, Y. Qiu, X. Cui, Y.P.S. Goh, J. Mwangi, T. David, L. Mukundan, F. Brombacher, R.M. Locksley, A. Chawla, Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis, Nature 480 (2011) 104–108, http://dx.doi.org/10.1038/nature10653. [15] K. Fischer, H.H. Ruiz, K. Jhun, B. Finan, D.J. Oberlin, V. van der Heide, A.V. Kalinovich, N. Petrovic, Y. Wolf, C. Clemmensen, A.C. Shin, S. Divanovic, F. Brombacher, E. Glasmacher, S. Keipert, M. Jastroch, J. Nagler, K.-W. Schramm, D. Medrikova, G. Collden, S.C. Woods, S. Herzig, D. Homann, S. Jung, J. Nedergaard, B. Cannon, M.H. Tschöp, T.D. Müller, C. Buettner, Alternatively activated macrophages do not synthesize catecholamines or contribute to adipose tissue adaptive thermogenesis, Nat. Med. (2017), http://dx.doi.org/10.1038/nm. 4316. [16] K.-J. Chung, A. Chatzigeorgiou, M. Economopoulou, R. Garcia-Martin, V.I. Alexaki, I. Mitroulis, M. Nati, J. Gebler, T. Ziemssen, S.E. Goelz, J. Phieler, J.-H. Lim, K.P. Karalis, T. Papayannopoulou, M. Blüher, G. Hajishengallis, T. Chavakis, A selfsustained loop of inflammation-driven inhibition of beige adipogenesis in obesity, Nat. Immunol. (2017), http://dx.doi.org/10.1038/ni.3728. [17] W. Ying, M. Riopel, G. Bandyopadhyay, Y. Dong, A. Birmingham, J.B. Seo, J.M. Ofrecio, J. Wollam, A. Hernandez-Carretero, W. Fu, P. Li, J.M. Olefsky, Adipose tissue macrophage-derived exosomal miRNAs can modulate in vivo and in vitro insulin sensitivity, Cell 171 (2017), http://dx.doi.org/10.1016/j.cell.2017.08. 035 372–378.e12. [18] T. Smallie, G. Ricchetti, N.J. Horwood, M. Feldmann, A.R. Clark, L.M. Williams, IL10 inhibits transcription elongation of the human TNF gene in primary macrophages, J. Exp. Med. 207 (2010) 2081–2088, http://dx.doi.org/10.1084/jem. 20100414.
5
Cellular Immunology xxx (xxxx) xxx–xxx
L. Catrysse, G. van Loo
2012.06.016. [40] Y. Ji, S. Sun, A. Xu, P. Bhargava, L. Yang, K.S.L. Lam, B. Gao, C.H. Lee, S. Kersten, L. Qi, Activation of natural killer T cells promotes M2 macrophage polarization in adipose tissue and improves systemic glucose tolerance via interleukin-4 (IL-4)/ STAT6 protein signaling axis in obesity, J. Biol. Chem. 287 (2012) 13561–13571, http://dx.doi.org/10.1074/jbc.M112.350066. [41] J.Y. Huh, J. Park, J.I. Kim, Y.J. Park, Y.K. Lee, J.B. Kim, Deletion of CD1d in adipocytes aggravates adipose tissue inflammation and insulin resistance in obesity, Diabetes 66 (2017) 835–847, http://dx.doi.org/10.2337/db16-1122. [42] H. Zhang, R. Xue, S. Zhu, S. Fu, Z. Chen, R. Zhou, Z. Tian, L. Bai, M2-specific reduction of CD1d switches NKT cell-mediated immune responses and triggers metaflammation in adipose tissue, Nat. Publ. Gr. (2017), http://dx.doi.org/10. 1038/cmi.2017.11. [43] S. Boulenouar, X. Michelet, D. Duquette, M.B. Brenner, U. Von Andrian, S. Boulenouar, X. Michelet, D. Duquette, D. Alvarez, A.E. Hogan, C. Dold, D.O. Connor, S. Stutte, A. Tavakkoli, D. Winters, M.A. Exley, D.O. Shea, M.B. Brenner, U. Von Andrian, L. Lynch, Adipose type one innate lymphoid cells regulate macrophage homeostasis through targeted article adipose type one innate lymphoid cells regulate macrophage homeostasis through targeted cytotoxicity, Immunity 46 (2017) 273–286, http://dx.doi.org/10.1016/j.immuni.2017.01.008. [44] A.B. Molofsky, J.C. Nussbaum, H.-E. Liang, S.J. Van Dyken, L.E. Cheng, A. Mohapatra, A. Chawla, R.M. Locksley, Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages, J. Exp. Med. 210 (2013) 535–549, http://dx.doi.org/10.1084/jem.20121964. [45] J.R. Brestoff, B.S. Kim, S.A. Saenz, R.R. Stine, L.A. Monticelli, G.F. Sonnenberg, J.J. Thome, D.L. Farber, K. Lutfy, P. Seale, D. Artis, Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity, Nature 519 (2015) 242–246, http://dx.doi.org/10.1038/nature14115. [46] E. Hams, R.M. Locksley, A.N.J. McKenzie, P.G. Fallon, Cutting edge: IL-25 elicits innate lymphoid type 2 and type II NKT cells that regulate obesity in mice, J. Immunol. 191 (2013) 5349–5353, http://dx.doi.org/10.4049/jimmunol.1301176. [47] V. Elgazar-Carmon, A. Rudich, N. Hadad, R. Levy, Neutrophils transiently infiltrate intra-abdominal fat early in the course of high-fat feeding, J. Lipid Res. 49 (2008) 1894–1903, http://dx.doi.org/10.1194/jlr.M800132-JLR200. [48] S. Talukdar, D.Y. Oh, G. Bandyopadhyay, D. Li, J. Xu, J. McNelis, M. Lu, P. Li, Q. Yan, Y. Zhu, J. Ofrecio, M. Lin, M.B. Brenner, J.M. Olefsky, Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase, Nat. Med. 18 (2012) 1407–1412, http://dx.doi.org/10.1038/nm.2885. [49] D.A. Winer, S. Winer, L. Shen, P.P. Wadia, J. Yantha, G. Paltser, H. Tsui, P. Wu, M.G. Davidson, M.N. Alonso, H.X. Leong, A. Glassford, M. Caimol, J.A. Kenkel, T.F. Tedder, T. McLaughlin, D.B. Miklos, H.-M. Dosch, E.G. Engleman, B cells
[50]
[51]
[52]
[53]
[54]
[55]
[56]
[57]
[58]
6
promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies, Nat. Med. 17 (2011) 610–617, http://dx.doi.org/10.1038/ nm.2353. S. Nishimura, I. Manabe, M. Nagasaki, K. Eto, H. Yamashita, M. Ohsugi, M. Otsu, K. Hara, K. Ueki, S. Sugiura, K. Yoshimura, T. Kadowaki, R. Nagai, CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity, Nat. Med. 15 (2009) 914–920, http://dx.doi.org/10.1038/nm.1964. V.Z. Rocha, E.J. Folco, G. Sukhova, K. Shimizu, I. Gotsman, A.H. Vernon, P. Libby, Interferon-γ, a Th1 cytokine, regulates fat inflammation: a role for adaptive immunity in obesity, Circ. Res. 103 (2008) 467–476, http://dx.doi.org/10.1161/ CIRCRESAHA.108.177105. L. Pacifico, L. Di Renzo, C. Anania, J.F. Osborn, F. Ippoliti, E. Schiavo, C. Chiesa, Increased T-helper interferon-gamma-secreting cells in obese children, Eur. J. Endocrinol. 154 (2006) 691–697, http://dx.doi.org/10.1530/eje.1.02138. B.-C. Lee, M.-S. Kim, M. Pae, Y. Yamamoto, D. Eberlé, T. Shimada, N. Kamei, H.S. Park, S. Sasorith, J.R. Woo, J. You, W. Mosher, H.J.M. Brady, S.E. Shoelson, J. Lee, Adipose natural killer cells regulate adipose tissue macrophages to promote insulin resistance in obesity, Cell Metab. (2016) 685–698, http://dx.doi.org/10. 1016/j.cmet.2016.03.002. R.W. O’Rourke, K.A. Meyer, C.K. Neeley, G.D. Gaston, P. Sekhri, M. Szumowski, B. Zamarron, C.N. Lumeng, D.L. Marks, Systemic NK cell ablation attenuates intraabdominal adipose tissue macrophage infiltration in murine obesity, Obesity 22 (2014) 2109–2114, http://dx.doi.org/10.1002/oby.20823. F.M. Wensveen, V. Jelenčić, S. Valentić, M. Šestan, T.T. Wensveen, S. Theurich, A. Glasner, D. Mendrila, D. Štimac, F.T. Wunderlich, J.C. Brüning, O. Mandelboim, B. Polić, NK cells link obesity-induced adipose stress to inflammation and insulin resistance, Nat. Immunol. 16 (2015) 376–385, http://dx.doi.org/10.1038/ni.3120. M.J. Kraakman, A.J. Murphy, K. Jandeleit-Dahm, H.L. Kammoun, Macrophage polarization in obesity and type 2 diabetes: weighing down our understanding of macrophage function? Front. Immunol. 5 (2014), http://dx.doi.org/10.3389/ fimmu.2014.00470. X. Xu, A. Grijalva, A. Skowronski, M. van Eijk, M.J. Serlie, A.W. Ferrante, Obesity activates a program of lysosomal-dependent lipid metabolism in adipose tissue macrophages independently of classic activation, Cell Metab. 18 (2013) 816–830, http://dx.doi.org/10.1016/j.cmet.2013.11.001. M. Kratz, B.R. Coats, K.B. Hisert, D. Hagman, V. Mutskov, E. Peris, K.Q. Schoenfelt, J.N. Kuzma, I. Larson, P.S. Billing, R.W. Landerholm, M. Crouthamel, D. Gozal, S. Hwang, P.K. Singh, L. Becker, Metabolic dysfunction drives a mechanistically distinct proinflammatory phenotype in adipose tissue macrophages, Cell Metab. 20 (2014) 614–625, http://dx.doi.org/10.1016/j.cmet.2014.08.010.