n e ws and vi e ws
Countering inflammatory signals in obesity Shannon M Reilly & Alan R Saltiel Although it is generally considered a proinflammatory cytokine, interleukin 6 (IL-6) has anti-inflammatory effects in macrophages by sensitizing them to IL-4 through upregulation of the IL-4 receptor. nvestigation into the many complications of obesity have suggested that activation of the innate immune system may be a common unifying feature of the disease. Both genetic forms and dietary forms of obesity in rodents are accompanied by the generation of low-grade, chronic inflammation in adipose and liver tissue1, and a strong correlation between resistance to insulin and the expression of inflammatory markers has been demonstrated in studies of several patient groups2. Furthermore, inflammation may be a key causal link between obesity and resistance to insulin, as inhibition of inflammatory signaling through the deletion of genes encoding molecules essential to key pathways in obese mice, as well as the administration of various anti-inflammatory pharmacological agents to rodents and patients with type 2 diabetes, can diminish resistance to insulin3. Despite the accumulation of such insights, the roles of individual cytokines in that process remain uncertain; one of the most confusing of those is interleukin 6 (IL-6). In this issue of Nature Immunology, Mauer et al. shed some light on this puzzle by providing new information on how IL-6 might control macrophage activity and thus affect metabolic health4. Many studies have now shown that obesityassociated inflammation is accompanied by the switching of macrophages in both adipose tissue and liver from a type 2 (M2) polarization state, generally associated with tissue surveillance and enhanced sensitivity to insulin, to a type 1 (M1) polarization state, characterized by the secretion of proinflammatory cytokines that attenuate the action of insulin5,6. However, while an increase in the abundance of M1-polarized macrophages in adipose tissue occurs as a consequence of the infiltration of new cells, the abundance and activity of M2 macrophages seems to remain constant during obesity. Moreover, while alterations in the abundance and polarization state of macrophages in adipose tissue seem to occur coincident with the development of resistance to insulin, other changes in the innate immune Shannon M. Reilly and Alan R. Saltiel are with the Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, USA. e-mail: [email protected]
410
system may precede those events, and macrophages in adipose tissue may be the effectors of a coordinated inflammatory response that includes crosstalk among T cells, B cells, natural killer cells, natural killer T cells, eosinophils, neutrophils and mast cells1. How are all those complex interactions in the innate immune system triggered during obesity, and what is responsible for the sustained low-grade nature of the response? While the inflammatory response of obesity includes most of the expected cell types, it lacks many of the cardinal signs of classic inflammation, which suggests there may be counterregulatory events that attenuate the extent to which inflammatory signals are effective. One such potential mechanism, secretion of the cytokine IL-6, is highlighted in the article by Mauer et al.4. IL-6 has a long and somewhat confusing history in metabolic disease. Some studies have indicated that IL-6 is more abundant in obesity and this may correlate with resistance to insulin2 and that IL-6 might have a causal role in producing resistance to insulin, mainly through induction of the inhibitory regulator SOCS3 in liver7. However, other studies have shown that mice deficient in IL-6 are susceptible to resistance to insulin and type 2 diabetes8. Mauer et al. wade into this controversy by evaluating mice with IL-6
M2 TNF
Muscle
IL-4
↑IL-4Rα
M1
conditional deletion (specifically in myeloid cells) of Il6ra, which encodes the α-chain of the receptor for IL-6, to assess the action of IL-6 in macrophages4. Surprisingly, these mice exhibit enhanced sensitivity to the metabolic effects of a high-fat diet, with worsened resistance to insulin in both fat and liver, along with systemic changes in tolerance to glucose and insulin; this suggests that IL-6 might provide an overall beneficial effect exerted at least partially through cells of the myeloid lineage. Several published studies have indicated that IL-6 might potentiate or even mimic some of insulin’s actions in liver9; however, the role of IL-6 in myeloid cells has not been elucidated. Mauer et al. analyze gene expression in liver and visceral white adipose tissue and find higher expression of many genes encoding inflammatory molecules associated with the M1 macrophage phenotype, accompanied by lower expression of M2 macrophage– associated genes, in both tissues from mice with myeloid cell–specific deletion of Il6ra than in wild-type control mice4. To determine whether cell-autonomous mechanisms underlie that phenomenon, Mauer et al. analyze bone marrow–derived macrophages treated with IL-6. They find many genes with different expression in IL-6-treated Il6ra-deficient cells than in their control counterparts, but one that
Eosinophil
Exercise IL-6
IL-10 Insulin
Insulin Sympathetic activation
IL-6
Liver Adipocytes
Figure 1 The paradoxical role of IL-6 in regulating metabolic homeostasis. IL-6 can be secreted from macrophages, adipocytes and skeletal muscle and in turn can influence metabolic disease. This cytokine is produced in skeletal muscles after acute exercise or in brown and beige adipocytes after activation by catecholamines and in turn regulates the hepatic expression of genes encoding gluconeogenic molecules to decrease the concentration of sugar in the blood. IL-6 can also be secreted from M1-polarized proinflammatory macrophages by pathways associated with obesity, such as NF-κB, and can in turn promote higher expression of genes associated with the M2 phenotype, including Il4ra (which encodes the receptor IL-4Rα). Upregulation of Il4ra sensitizes macrophages to the effects of IL-4 secreted from eosinophils in adipose tissue and promotes an increase in the sensitivity of adipocytes and perhaps hepatocytes to insulin through the secretion of IL-10 or via other anti-inflammatory signals. Thus, although IL-6 is secreted in response to catabolic signals, it seems to exert an overall anabolic effect that directs increased storage of energy; this suggests it serves a feedback role in metabolism.
Katie Vicari
npg
© 2014 Nature America, Inc. All rights reserved.
I
volume 15 number 5 may 2014 nature immunology
npg
© 2014 Nature America, Inc. All rights reserved.
n e ws and vi e ws stands out is the gene encoding the α-chain of the receptor for IL-4 (Il4ra)4. IL-6 directly increases Il4ra expression in macrophages via phosphorylation of the transcription factor STAT3 and subsequent regulation of the Il4ra promoter. This is of particular interest because IL-4 is secreted from T cells or eosinophils in adipose tissue and in turn promotes the M2 polarization of macrophages10. That is accompanied by increased expression of many genes encoding molecules (particularly IL-10) that contribute to greater sensitivity to insulin in adipocytes5. Together these data suggest that IL-6 may influence sensitivity to insulin in liver and fat by promoting a switch in macrophage polarization from a proinflammatory M1 phenotype to an anti-inflammatory M2 phenotype4. While those data further support the proposal that IL-6 serves a beneficial role in the regulation of metabolism, several questions remain about a teleological explanation for those observations. IL-6 itself is generated as a part of the inflammatory program, and its expression in myeloid cells and other cells is known to be controlled by inflammatory signals such as those from the transcription factor NF-κB11 and by catabolic hormones
and biogenic amines that increase the concentration of cAMP12. Since the upstream signals that increase the secretion of IL-6 generally oppose the action of insulin, it seems reasonable to conclude that IL-6 may in this case act as a feedback regulator, attenuating inflammatory and catabolic signaling to preserve the action of insulin. Such a ‘counterinflammatory’ role for IL-6 is consistent with other feedback signals that might serve to limit inflammation in obesity and thus promote the storage of energy in the face of the catabolic pressure of inflammation. Another question is about the relevance of the various tissues from which IL-6 is secreted and how this influences metabolic homeostasis (Fig. 1). Several studies have demonstrated that IL-6 is secreted from skeletal muscle in response to exercise and from brown or white fat depots in response to sympathetic activation. Not only is IL-6 secreted from various metabolically active tissues but it also has important metabolic effects in those tissues. IL-6 can diminish the hepatic expression of genes encoding gluconeogenic molecules to decrease the concentration of sugar in the blood during the fasting state, an effect presumably independent of the innate immune
system9. Thus, the crucial sites for the secretion and action of IL-6 remain uncertain, and the observation that this cytokine is apparently produced in response to proinflammatory and catabolic signaling to produce antiinflammatory and anabolic effects is itself paradoxical. Thus, some of the confusion about the metabolic role of this interesting cytokine might persist for a while longer. COMPETING FINANCIAL INTERESTS The authors declare no competing financial interests. 1. Lumeng, C.N. & Saltiel, A.R. J. Clin. Invest. 121, 2111–2117 (2011). 2. Pradhan, A.D. et al. J. Am. Med. Assoc. 286, 327–334 (2001). 3. Goldfine, A.B. et al. Ann. Intern. Med. 152, 346–357 (2010). 4. Mauer, J. et al. Nat. Immunol. 15, 423–430 (2014). 5. Lumeng, C.N., Bodzin, J.L. & Saltiel, A.R. J. Clin. Invest. 117, 175–184 (2007). 6. Schenk, S., Saberi, M. & Olefsky, J.M. J. Clin. Invest. 118, 2992–3002 (2008). 7. Ueki, K. et al. Proc. Natl. Acad. Sci. USA 101, 10422–10427 (2004). 8. Wallenius, V. et al. Nat. Med. 8, 75–79 (2002). 9. Stanford, K.I. et al. J. Clin. Invest. 123, 215–223 (2013). 10. Wu, D. et al. Science 332, 243–247 (2011). 11. Cai, D. et al. Nat. Med. 11, 183–190 (2005). 12. Burýsek, L. & Houstek, J. FEBS Lett. 411, 83–86 (1997).
SGK1: master and commander of the fate of helper T cells Matthew Norton & Robert A Screaton Cytokines and other environmental cues influence polarization of CD4+ helper T cells, but the signaling pathways that are involved are less clear. Recent findings show that signaling via an mTORC2-SGK1 kinase axis regulates TH12TH2 cell-fate polarization.
I
mmunity is classified into the innate and adaptive systems, which oversee the immediate nonspecific responses to pathogens and the acquired, highly specific and long-term responses to pathogens, respectively. Naive CD4+ T cells are derived from the thymus and, after being activated by antigen-specific cues in the periphery, can differentiate into the TH1, TH2 or TH17 lineage of effector helper T cells. The TH1 and TH2 subsets define two classes of CD4+ helper T cells and control Matthew Norton is with the Children’s Hospital of Eastern Ontario Research Institute, Ottawa, Canada. Robert A. Screaton is with the Children’s Hospital of Eastern Ontario Research Institute, Ottawa, Canada, and the Department of Cellular and Molecular Medicine and Department of Pediatrics, University of Ottawa, Ottawa, Canada. e-mail: [email protected]
cell-mediated immunity to pathogens and extracellular immunity to pathogens, respectively. Over-reactive TH1 cells are associated with organ-specific autoimmunity, such as multiple sclerosis and type 1 diabetes mellitus, while TH2 cells are associated with the pathology of allergic asthma1. While current therapy for asthma focuses on relieving symptoms, earlier therapeutic intervention to diminish skewing toward TH2 cell–mediated immune responses may lead to better responses in patients2. As those conditions affect hundreds of millions of people worldwide, improved understanding of the mechanisms of T cell determination holds the promise of novel therapies for those affected. In this issue of Nature Immunology, Powell and colleagues report that the serumand glucocorticoid-regulated kinase SGK1 is a critical determinant of the developmental fate of T cells that functions to promote differentiation
nature immunology volume 15 number 5 may 2014
into the TH2 lineage while simultaneously blocking differentiation into the TH1 lineage3. SGK1 belongs to the AGC family of kinases, which features the iconic members Akt and S6K; these collectively relay extracellular signals designed to elicit cellular growth, proliferation and survival responses. SGK1 is a downstream target of the metabolic checkpoint kinase complex mTORC2; it is thought to regulate the expression of sodium channels in the kidney and has garnered attention as a critical mediator of the pathogenic actions of TH17 cells4–6. This new work from Powell and colleagues3 expands the understanding of the biological roles of SGK1 to include determining the fate of CD4+ helper T cells. While commitment to the TH1 lineage or TH2 lineage is known to be regulated by defined cytokines and transcription factors, Powell and colleagues3 describe a signaling pathway that may 411
Countering inflammatory signals in obesity Shannon M Reilly & Alan R Saltiel Although it is generally considered a proinflammatory cytokine, interleukin 6 (IL-6) has anti-inflammatory effects in macrophages by sensitizing them to IL-4 through upregulation of the IL-4 receptor. nvestigation into the many complications of obesity have suggested that activation of the innate immune system may be a common unifying feature of the disease. Both genetic forms and dietary forms of obesity in rodents are accompanied by the generation of low-grade, chronic inflammation in adipose and liver tissue1, and a strong correlation between resistance to insulin and the expression of inflammatory markers has been demonstrated in studies of several patient groups2. Furthermore, inflammation may be a key causal link between obesity and resistance to insulin, as inhibition of inflammatory signaling through the deletion of genes encoding molecules essential to key pathways in obese mice, as well as the administration of various anti-inflammatory pharmacological agents to rodents and patients with type 2 diabetes, can diminish resistance to insulin3. Despite the accumulation of such insights, the roles of individual cytokines in that process remain uncertain; one of the most confusing of those is interleukin 6 (IL-6). In this issue of Nature Immunology, Mauer et al. shed some light on this puzzle by providing new information on how IL-6 might control macrophage activity and thus affect metabolic health4. Many studies have now shown that obesityassociated inflammation is accompanied by the switching of macrophages in both adipose tissue and liver from a type 2 (M2) polarization state, generally associated with tissue surveillance and enhanced sensitivity to insulin, to a type 1 (M1) polarization state, characterized by the secretion of proinflammatory cytokines that attenuate the action of insulin5,6. However, while an increase in the abundance of M1-polarized macrophages in adipose tissue occurs as a consequence of the infiltration of new cells, the abundance and activity of M2 macrophages seems to remain constant during obesity. Moreover, while alterations in the abundance and polarization state of macrophages in adipose tissue seem to occur coincident with the development of resistance to insulin, other changes in the innate immune Shannon M. Reilly and Alan R. Saltiel are with the Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, USA. e-mail: [email protected]
410
system may precede those events, and macrophages in adipose tissue may be the effectors of a coordinated inflammatory response that includes crosstalk among T cells, B cells, natural killer cells, natural killer T cells, eosinophils, neutrophils and mast cells1. How are all those complex interactions in the innate immune system triggered during obesity, and what is responsible for the sustained low-grade nature of the response? While the inflammatory response of obesity includes most of the expected cell types, it lacks many of the cardinal signs of classic inflammation, which suggests there may be counterregulatory events that attenuate the extent to which inflammatory signals are effective. One such potential mechanism, secretion of the cytokine IL-6, is highlighted in the article by Mauer et al.4. IL-6 has a long and somewhat confusing history in metabolic disease. Some studies have indicated that IL-6 is more abundant in obesity and this may correlate with resistance to insulin2 and that IL-6 might have a causal role in producing resistance to insulin, mainly through induction of the inhibitory regulator SOCS3 in liver7. However, other studies have shown that mice deficient in IL-6 are susceptible to resistance to insulin and type 2 diabetes8. Mauer et al. wade into this controversy by evaluating mice with IL-6
M2 TNF
Muscle
IL-4
↑IL-4Rα
M1
conditional deletion (specifically in myeloid cells) of Il6ra, which encodes the α-chain of the receptor for IL-6, to assess the action of IL-6 in macrophages4. Surprisingly, these mice exhibit enhanced sensitivity to the metabolic effects of a high-fat diet, with worsened resistance to insulin in both fat and liver, along with systemic changes in tolerance to glucose and insulin; this suggests that IL-6 might provide an overall beneficial effect exerted at least partially through cells of the myeloid lineage. Several published studies have indicated that IL-6 might potentiate or even mimic some of insulin’s actions in liver9; however, the role of IL-6 in myeloid cells has not been elucidated. Mauer et al. analyze gene expression in liver and visceral white adipose tissue and find higher expression of many genes encoding inflammatory molecules associated with the M1 macrophage phenotype, accompanied by lower expression of M2 macrophage– associated genes, in both tissues from mice with myeloid cell–specific deletion of Il6ra than in wild-type control mice4. To determine whether cell-autonomous mechanisms underlie that phenomenon, Mauer et al. analyze bone marrow–derived macrophages treated with IL-6. They find many genes with different expression in IL-6-treated Il6ra-deficient cells than in their control counterparts, but one that
Eosinophil
Exercise IL-6
IL-10 Insulin
Insulin Sympathetic activation
IL-6
Liver Adipocytes
Figure 1 The paradoxical role of IL-6 in regulating metabolic homeostasis. IL-6 can be secreted from macrophages, adipocytes and skeletal muscle and in turn can influence metabolic disease. This cytokine is produced in skeletal muscles after acute exercise or in brown and beige adipocytes after activation by catecholamines and in turn regulates the hepatic expression of genes encoding gluconeogenic molecules to decrease the concentration of sugar in the blood. IL-6 can also be secreted from M1-polarized proinflammatory macrophages by pathways associated with obesity, such as NF-κB, and can in turn promote higher expression of genes associated with the M2 phenotype, including Il4ra (which encodes the receptor IL-4Rα). Upregulation of Il4ra sensitizes macrophages to the effects of IL-4 secreted from eosinophils in adipose tissue and promotes an increase in the sensitivity of adipocytes and perhaps hepatocytes to insulin through the secretion of IL-10 or via other anti-inflammatory signals. Thus, although IL-6 is secreted in response to catabolic signals, it seems to exert an overall anabolic effect that directs increased storage of energy; this suggests it serves a feedback role in metabolism.
Katie Vicari
npg
© 2014 Nature America, Inc. All rights reserved.
I
volume 15 number 5 may 2014 nature immunology
npg
© 2014 Nature America, Inc. All rights reserved.
n e ws and vi e ws stands out is the gene encoding the α-chain of the receptor for IL-4 (Il4ra)4. IL-6 directly increases Il4ra expression in macrophages via phosphorylation of the transcription factor STAT3 and subsequent regulation of the Il4ra promoter. This is of particular interest because IL-4 is secreted from T cells or eosinophils in adipose tissue and in turn promotes the M2 polarization of macrophages10. That is accompanied by increased expression of many genes encoding molecules (particularly IL-10) that contribute to greater sensitivity to insulin in adipocytes5. Together these data suggest that IL-6 may influence sensitivity to insulin in liver and fat by promoting a switch in macrophage polarization from a proinflammatory M1 phenotype to an anti-inflammatory M2 phenotype4. While those data further support the proposal that IL-6 serves a beneficial role in the regulation of metabolism, several questions remain about a teleological explanation for those observations. IL-6 itself is generated as a part of the inflammatory program, and its expression in myeloid cells and other cells is known to be controlled by inflammatory signals such as those from the transcription factor NF-κB11 and by catabolic hormones
and biogenic amines that increase the concentration of cAMP12. Since the upstream signals that increase the secretion of IL-6 generally oppose the action of insulin, it seems reasonable to conclude that IL-6 may in this case act as a feedback regulator, attenuating inflammatory and catabolic signaling to preserve the action of insulin. Such a ‘counterinflammatory’ role for IL-6 is consistent with other feedback signals that might serve to limit inflammation in obesity and thus promote the storage of energy in the face of the catabolic pressure of inflammation. Another question is about the relevance of the various tissues from which IL-6 is secreted and how this influences metabolic homeostasis (Fig. 1). Several studies have demonstrated that IL-6 is secreted from skeletal muscle in response to exercise and from brown or white fat depots in response to sympathetic activation. Not only is IL-6 secreted from various metabolically active tissues but it also has important metabolic effects in those tissues. IL-6 can diminish the hepatic expression of genes encoding gluconeogenic molecules to decrease the concentration of sugar in the blood during the fasting state, an effect presumably independent of the innate immune
system9. Thus, the crucial sites for the secretion and action of IL-6 remain uncertain, and the observation that this cytokine is apparently produced in response to proinflammatory and catabolic signaling to produce antiinflammatory and anabolic effects is itself paradoxical. Thus, some of the confusion about the metabolic role of this interesting cytokine might persist for a while longer. COMPETING FINANCIAL INTERESTS The authors declare no competing financial interests. 1. Lumeng, C.N. & Saltiel, A.R. J. Clin. Invest. 121, 2111–2117 (2011). 2. Pradhan, A.D. et al. J. Am. Med. Assoc. 286, 327–334 (2001). 3. Goldfine, A.B. et al. Ann. Intern. Med. 152, 346–357 (2010). 4. Mauer, J. et al. Nat. Immunol. 15, 423–430 (2014). 5. Lumeng, C.N., Bodzin, J.L. & Saltiel, A.R. J. Clin. Invest. 117, 175–184 (2007). 6. Schenk, S., Saberi, M. & Olefsky, J.M. J. Clin. Invest. 118, 2992–3002 (2008). 7. Ueki, K. et al. Proc. Natl. Acad. Sci. USA 101, 10422–10427 (2004). 8. Wallenius, V. et al. Nat. Med. 8, 75–79 (2002). 9. Stanford, K.I. et al. J. Clin. Invest. 123, 215–223 (2013). 10. Wu, D. et al. Science 332, 243–247 (2011). 11. Cai, D. et al. Nat. Med. 11, 183–190 (2005). 12. Burýsek, L. & Houstek, J. FEBS Lett. 411, 83–86 (1997).
SGK1: master and commander of the fate of helper T cells Matthew Norton & Robert A Screaton Cytokines and other environmental cues influence polarization of CD4+ helper T cells, but the signaling pathways that are involved are less clear. Recent findings show that signaling via an mTORC2-SGK1 kinase axis regulates TH12TH2 cell-fate polarization.
I
mmunity is classified into the innate and adaptive systems, which oversee the immediate nonspecific responses to pathogens and the acquired, highly specific and long-term responses to pathogens, respectively. Naive CD4+ T cells are derived from the thymus and, after being activated by antigen-specific cues in the periphery, can differentiate into the TH1, TH2 or TH17 lineage of effector helper T cells. The TH1 and TH2 subsets define two classes of CD4+ helper T cells and control Matthew Norton is with the Children’s Hospital of Eastern Ontario Research Institute, Ottawa, Canada. Robert A. Screaton is with the Children’s Hospital of Eastern Ontario Research Institute, Ottawa, Canada, and the Department of Cellular and Molecular Medicine and Department of Pediatrics, University of Ottawa, Ottawa, Canada. e-mail: [email protected]
cell-mediated immunity to pathogens and extracellular immunity to pathogens, respectively. Over-reactive TH1 cells are associated with organ-specific autoimmunity, such as multiple sclerosis and type 1 diabetes mellitus, while TH2 cells are associated with the pathology of allergic asthma1. While current therapy for asthma focuses on relieving symptoms, earlier therapeutic intervention to diminish skewing toward TH2 cell–mediated immune responses may lead to better responses in patients2. As those conditions affect hundreds of millions of people worldwide, improved understanding of the mechanisms of T cell determination holds the promise of novel therapies for those affected. In this issue of Nature Immunology, Powell and colleagues report that the serumand glucocorticoid-regulated kinase SGK1 is a critical determinant of the developmental fate of T cells that functions to promote differentiation
nature immunology volume 15 number 5 may 2014
into the TH2 lineage while simultaneously blocking differentiation into the TH1 lineage3. SGK1 belongs to the AGC family of kinases, which features the iconic members Akt and S6K; these collectively relay extracellular signals designed to elicit cellular growth, proliferation and survival responses. SGK1 is a downstream target of the metabolic checkpoint kinase complex mTORC2; it is thought to regulate the expression of sodium channels in the kidney and has garnered attention as a critical mediator of the pathogenic actions of TH17 cells4–6. This new work from Powell and colleagues3 expands the understanding of the biological roles of SGK1 to include determining the fate of CD4+ helper T cells. While commitment to the TH1 lineage or TH2 lineage is known to be regulated by defined cytokines and transcription factors, Powell and colleagues3 describe a signaling pathway that may 411
