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The Semaphorin 3E/PlexinD1 Axis Regulates Macrophage Inflammation in Obesity

2013; Cell Press; Volume: 18; Issue: 4 Linguagem: Inglês

10.1016/j.cmet.2013.09.011

1932-7420

Ann Marie Schmidt, Kathryn J. Moore,

Lipid metabolism and disorders

Increased accumulation of adipose tissue macrophages in obesity propagates chronic inflammation that is closely associated with insulin resistance and type 2 diabetes. Semaphorin 3E, a guidance molecule for neurons, takes on a new role in obesity by directing the recruitment of macrophages in visceral adipose tissue (Shimizu et al., 2013Shimizu I. Yoshida Y. Moriya J. Nojima A. Uemura A. Kobayashi Y. Minamino T. Cell Metab. 2013; 18 (this issue): 491-504Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar). Increased accumulation of adipose tissue macrophages in obesity propagates chronic inflammation that is closely associated with insulin resistance and type 2 diabetes. Semaphorin 3E, a guidance molecule for neurons, takes on a new role in obesity by directing the recruitment of macrophages in visceral adipose tissue (Shimizu et al., 2013Shimizu I. Yoshida Y. Moriya J. Nojima A. Uemura A. Kobayashi Y. Minamino T. Cell Metab. 2013; 18 (this issue): 491-504Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar). Obesity, insulin resistance, and type 2 diabetes are increasing to epidemic proportions and are major contributors to morbidity and mortality worldwide. During obesity visceral adipose tissue is infiltrated by large numbers of immune cells, particularly macrophages, which incite metabolic dysregulation (Glass and Olefsky, 2012Glass C.K. Olefsky J.M. Cell Metab. 2012; 15: 635-645Abstract Full Text Full Text PDF PubMed Scopus (584) Google Scholar). The expanding adipose undergoes extensive remodeling, and this influx of macrophages likely helps to maintain tissue homeostasis, at least initially. However, these adipose tissue macrophages (ATMs) secrete proinflammatory cytokines, most notably tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6), which fuel chronic inflammation, contributing to the development of systemic insulin resistance (Glass and Olefsky, 2012Glass C.K. Olefsky J.M. Cell Metab. 2012; 15: 635-645Abstract Full Text Full Text PDF PubMed Scopus (584) Google Scholar). A new study by Shimizu et al., 2013Shimizu I. Yoshida Y. Moriya J. Nojima A. Uemura A. Kobayashi Y. Minamino T. Cell Metab. 2013; 18 (this issue): 491-504Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar identifies Semaphorin 3E, typically thought of as a developmental axon guiding cue, as a potent regulator of adipose tissue macrophage accumulation in obesity that contributes to systemic insulin resistance. Growing evidence supports the participation of neuronal guidance molecules in the regulation of the immune system where they exert diverse effects on leukocyte migration, adhesion, and inflammatory responses (Takamatsu and Kumanogoh, 2012Takamatsu H. Kumanogoh A. Trends Immunol. 2012; 33: 127-135Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar). The class 3 Semaphorins are highly conserved, secreted, and matrix-associated proteins that signal through various transmembrane receptors in the Plexin or Neuropilin family to mediate both repulsive and attractive signaling (Püschel, 1999Püschel A.W. Nat. Neurosci. 1999; 2: 777-778Crossref PubMed Scopus (14) Google Scholar). Shimizu et al. observed a selective increase in expression of one member of this class, Sema3e, in visceral adipose tissue of mice fed a high-fat diet and a parallel increase in serum Semaphorin 3E levels (Shimizu et al., 2013Shimizu I. Yoshida Y. Moriya J. Nojima A. Uemura A. Kobayashi Y. Minamino T. Cell Metab. 2013; 18 (this issue): 491-504Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar). Notably, Sema3e expression localized to adipocytes, whereas its receptor PlexinD1 was found on both adipocytes and accumulating macrophages. In vitro, Semaphorin 3E, acting via PlexinD1 and Neuropilin 1, was a potent inducer of macrophage migration and proinflammatory cytokine expression (Figure 1). Moreover, Semaphorin 3E inhibited insulin signaling in adipocytes by blocking Akt phosphorylation. Together, these findings suggested that secretion of Semaphorin 3E in expanding adipose promotes ATM and adipocyte pathogenic functions that contribute to insulin resistance. Indeed, overexpression of Sema3e using an adipocyte-specific promoter induced ATM accumulation, insulin resistance, and glucose intolerance in chow-fed mice, whereas global deletion of Sema3e improved diet-induced adipose inflammation and metabolic dysfunction. As observed in obese mice, individuals with diabetes show increased plasma levels of Semaphorin 3E indicating a potential role for Semaphorin 3E-plexinD1 signaling in human metabolic disease (Shimizu et al., 2013Shimizu I. Yoshida Y. Moriya J. Nojima A. Uemura A. Kobayashi Y. Minamino T. Cell Metab. 2013; 18 (this issue): 491-504Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar). In mice, delivery of a soluble form of plexinD1 was sufficient to counteract the effects of Semaphorin 3E in obesity, including ATM accumulation, insulin resistance, and glucose intolerance (Shimizu et al., 2013Shimizu I. Yoshida Y. Moriya J. Nojima A. Uemura A. Kobayashi Y. Minamino T. Cell Metab. 2013; 18 (this issue): 491-504Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar). Thus, counteracting the systemic effects of Semaphorin 3E may be sufficient to mitigate provocation of insulin resistance, at least in part by reducing the content of proinflammatory ATMs. Shimizu et al. also show that Semaphorin 3E/plexinD1 signaling increases markers of classically activated "M1" macrophages and p38 MAPK signaling, which promote proinflammatory responses. Increased activation of p38 has been observed in omental adipose tissue of human obese subjects (Bashan et al., 2007Bashan N. Dorfman K. Tarnovscki T. Harman-Boehm I. Liberty I.F. Blüher M. Ovadia S. Maymon-Zilberstein T. Potashnik R. Stumvoll M. et al.Endocrinology. 2007; 148: 2955-2962Crossref PubMed Scopus (95) Google Scholar), and in mice, treatment with p38 inhibitors suppressed obesity and insulin resistance triggered by consumption of a high-fat diet (Maekawa et al., 2010Maekawa T. Jin W. Ishii S. Mol. Cell. Biol. 2010; 30: 613-625Crossref PubMed Scopus (63) Google Scholar). To understand the mechanisms of Semaphorin 3E upregulation, the authors turned to the cancer field where Sema3 family members are known to be induced by the tumor suppressor p53. p53 is regulated by a variety of stress signals, including the accumulation of reactive oxygen species and DNA damage that characterize expanding adipose tissue. Indeed, HFD-fed mice with adipocyte-selective deficiency of p53 showed reduced expression of Sema3e and Plxnd1, which correlated with a decrease in macrophage infiltration and insulin resistance (Shimizu et al., 2013Shimizu I. Yoshida Y. Moriya J. Nojima A. Uemura A. Kobayashi Y. Minamino T. Cell Metab. 2013; 18 (this issue): 491-504Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar). Conversely, administration of a p53 activator to chow-fed mice was sufficient to incite adipocyte Sema3e expression and adipose tissue inflammation. This mechanism may be relevant to the recent link of adiposity to aging, which is associated with increased p53-transcriptional activity; however, this awaits further studies. Recent studies have demonstrated roles for Semaphorin 3E in the pathogenesis of other chronic inflammatory diseases, including rheumatoid arthritis (Mangasser-Stephan et al., 1997Mangasser-Stephan K. Dooley S. Welter C. Mutschler W. Hanselmann R.G. Biochem. Biophys. Res. Commun. 1997; 234: 153-156Crossref PubMed Scopus (37) Google Scholar) and atherosclerosis (Wanschel et al., 2013Wanschel A. Seibert T. Hewing B. Ramkhelawon B. Ray T.D. van Gils J.M. Rayner K.J. Feig J.E. O'Brien E.R. Fisher E.A. Moore K.J. Arterioscler. Thromb. Vasc. Biol. 2013; 33: 886-893Crossref PubMed Scopus (95) Google Scholar). Indeed, a comparison of the expression profiles of macrophages in progressing or regressing atherosclerotic plaques identified Sema3e as one of the genes most highly downregulated during the resolution of atherosclerotic inflammation (Feig et al., 2012Feig J.E. Vengrenyuk Y. Reiser V. Wu C. Statnikov A. Aliferis C.F. Garabedian M.J. Fisher E.A. Puig O. PLoS ONE. 2012; 7: e39790Crossref PubMed Scopus (87) Google Scholar). Furthermore Sema3e was upregulated in macrophages by oxidized low-density lipoprotein (LDL) and hypoxia, and its expression was associated with inflammatory M1 but not the alternatively activated M2 macrophages (Wanschel et al., 2013Wanschel A. Seibert T. Hewing B. Ramkhelawon B. Ray T.D. van Gils J.M. Rayner K.J. Feig J.E. O'Brien E.R. Fisher E.A. Moore K.J. Arterioscler. Thromb. Vasc. Biol. 2013; 33: 886-893Crossref PubMed Scopus (95) Google Scholar). This is relevant to adipose inflammation, where there is a shift from the reparative M2 macrophage phenotype in lean adipose to a predominantly M1 macrophage population, which secretes the proinflammatory cytokines that promote insulin resistance. Interestingly, Semaphorin 3E was explored as a macrophage retention molecule in the context of atherosclerosis and was shown to block the response of macrophages to chemokines (CCL19, CCL21) that have been implicated in the exodus of macrophages from plaques (Wanschel et al., 2013Wanschel A. Seibert T. Hewing B. Ramkhelawon B. Ray T.D. van Gils J.M. Rayner K.J. Feig J.E. O'Brien E.R. Fisher E.A. Moore K.J. Arterioscler. Thromb. Vasc. Biol. 2013; 33: 886-893Crossref PubMed Scopus (95) Google Scholar). Whether Semaphorin 3E plays a similar role in macrophage retention in adipose tissue remains unknown. Future studies of macrophage trafficking will be needed to determine whether Semaphorin 3E promotes macrophage accumulation in the obese adipose tissue by inciting the recruitment of monocytes or by providing a "stop" signal to retain cells in this inflammatory site. Furthermore, it will be of interest to determine how Semaphorin 3E coordinates monocyte and macrophage trafficking with other chemotactic signals, particularly CCL2, which is known to play a role in the recruitment of macrophages into adipose tissue. Given the bifunctional nature of Semaphorin 3E, one attractive hypothesis is that it switches between exerting repulsive or attractive effects by engaging different receptors or signaling pathways in macrophages. Such a scenario would allow for monocytes to be attracted to the site of inflammation, and then upon resolution, to be directed from the tissue. An open question therefore is, might soluble forms of plexinD1 be potential therapeutic strategies in obesity? In this context, it is important to ask, to what extent does the Semaphorin 3E/plexinD1 signaling family contribute to different inflammatory responses, in which a balance of proinflammatory and prorepair signals by macrophages are essential for clearance of pathogens and resolution of tissue inflammation? In the case of Semaphorin 3A/plexinA4, this pathway exacerbates the "cytokine storm" induced by Toll-like receptor agonists in a murine model of severe sepsis (Wen et al., 2010Wen H. Lei Y. Eun S.Y. Ting J.P. J. Exp. Med. 2010; 207: 2943-2957Crossref PubMed Scopus (85) Google Scholar). Although further studies are required to discern the possible therapeutic opportunities in obesity for Semaphorin 3E /plexinD1, the study by Shimizu et al. highlights the expanding functions of such guidance cues, whose actions were previously thought to be restricted to the nervous system, in regulating immune cell function and inflammatory responses. Semaphorin3E-Induced Inflammation Contributes to Insulin Resistance in Dietary ObesityShimizu et al.Cell MetabolismOctober 01, 2013In BriefSemaphorins and their receptors (plexins) are axon-guiding molecules that regulate the development of the nervous system during embryogenesis. Here we describe a previously unknown role of class 3 semaphorin E (Sema3E) in adipose tissue inflammation and insulin resistance. Expression of Sema3E and its receptor plexinD1 was upregulated in the adipose tissue of a mouse model of dietary obesity. Inhibition of the Sema3E-plexinD1 axis markedly reduced adipose tissue inflammation and improved insulin resistance in this model. Full-Text PDF Open Archive