RESEARCH HIGHLIGHTS
NPG
Nature Reviews Immunology | AOP, published online 22 April 2014; doi:10.1038/nri3670
I M M U N O M E TA B O L I S M
IL‑6, the resistance fighter
IL‑6R signalling in myeloid cells ... limits the development of insulin resistance during obesity
Increased levels of interleukin‑6 (IL‑6) are detected in the circulation of obese individuals, but it has been unclear whether this pleiotropic cytokine has beneficial or detri‑ mental effects in this setting. Now, Mauer et al. report that IL‑6 receptor (IL‑6R) signalling in myeloid cells has protective anti-inflammatory effects and limits the development of insulin resistance during obesity. The authors generated mice with a myeloid cell-specific deletion of the IL‑6Rα chain (Il6raΔmyel mice) and monitored weight gain in these animals in response to a normal chow diet or a high-fat diet (HFD). As expected, Il6raΔmyel mice gained more weight when fed a HFD than when fed a normal chow diet, but they showed comparable body weights, body fat content and serum leptin concentrations to control mice
that were maintained on an equiva‑ lent diet. However, Il6raΔmyel mice developed greater levels of glucose intolerance and insulin resistance in response to a HFD and showed mark‑ edly lower insulin-induced glucose uptake in white and brown adipose tissues. Insulin-mediated suppression of lipolysis and of hepatic glucose production was impaired in Il6raΔmyel mice fed a HFD, and these animals also had higher levels of triglycerides in the liver compared with controls. Disruption of IL‑6R signalling in myeloid cells was also associated with the development of increased systemic inflammation in response to a HFD. Compared with controls, Il6raΔmyel mice on a HFD showed increased activation of JUN N-terminal kinase (JNK) in the liver and adipose tissues, and had higher expression of genes that
NATURE REVIEWS | IMMUNOLOGY
encode pro-inflammatory cytokines and chemokines. Furthermore, the absence of IL‑6R signalling in macrophages increased their skew‑ ing towards a pro-inflammatory ‘M1 phenotype’ in mice that were fed a HFD. Notably, such differences were not seen in mice that were maintained on a normal chow diet. Additional experiments showed that IL‑6 promotes an alternatively activated ‘M2 phenotype’ in macro phages by upregulating the expression of the IL‑4R. IL‑6 induced IL‑4R expression in macrophages in a signal transducer and activator of transcrip‑ tion 3 (STAT3)-dependent manner; as such, IL‑6 promoted IL‑4R signal‑ ling and augmented IL‑4‑mediated STAT6 phosphorylation. In line with these findings, the authors found that IL‑4 treatment improved glucose tolerance in wild-type animals on a HFD, but was less effective in preventing the development of insulin resistance in Il6raΔmyel mice that were fed a HFD. Finally, they found that IL‑6R signalling limits the expression of pro-inflammatory genes in lipopolysaccharide (LPS)stimulated macrophages and showed that Il6raΔmyel mice were more sensitive to LPS-induced endotoxaemia than control mice. The authors conclude that the increased production of IL‑6 that occurs during obesity skews macro phages towards a less inflammatory M2 phenotype, thereby limiting the development of insulin resistance. It will be interesting to examine whether similar beneficial effects of IL‑6 are seen in the setting of human obesity. Yvonne Bordon ORIGINAL RESEARCH PAPER Mauer, J. et al. Signaling by IL‑6 promotes alternative activation of macrophages to limit endotoxemia and obesityassociated resistance to insulin. Nature Immunol. http://dx.doi.org/10.1038/ni.2865 (2014)
VOLUME 14 | MAY 2014 © 2014 Macmillan Publishers Limited. All rights reserved
NPG
Nature Reviews Immunology | AOP, published online 22 April 2014; doi:10.1038/nri3670
I M M U N O M E TA B O L I S M
IL‑6, the resistance fighter
IL‑6R signalling in myeloid cells ... limits the development of insulin resistance during obesity
Increased levels of interleukin‑6 (IL‑6) are detected in the circulation of obese individuals, but it has been unclear whether this pleiotropic cytokine has beneficial or detri‑ mental effects in this setting. Now, Mauer et al. report that IL‑6 receptor (IL‑6R) signalling in myeloid cells has protective anti-inflammatory effects and limits the development of insulin resistance during obesity. The authors generated mice with a myeloid cell-specific deletion of the IL‑6Rα chain (Il6raΔmyel mice) and monitored weight gain in these animals in response to a normal chow diet or a high-fat diet (HFD). As expected, Il6raΔmyel mice gained more weight when fed a HFD than when fed a normal chow diet, but they showed comparable body weights, body fat content and serum leptin concentrations to control mice
that were maintained on an equiva‑ lent diet. However, Il6raΔmyel mice developed greater levels of glucose intolerance and insulin resistance in response to a HFD and showed mark‑ edly lower insulin-induced glucose uptake in white and brown adipose tissues. Insulin-mediated suppression of lipolysis and of hepatic glucose production was impaired in Il6raΔmyel mice fed a HFD, and these animals also had higher levels of triglycerides in the liver compared with controls. Disruption of IL‑6R signalling in myeloid cells was also associated with the development of increased systemic inflammation in response to a HFD. Compared with controls, Il6raΔmyel mice on a HFD showed increased activation of JUN N-terminal kinase (JNK) in the liver and adipose tissues, and had higher expression of genes that
NATURE REVIEWS | IMMUNOLOGY
encode pro-inflammatory cytokines and chemokines. Furthermore, the absence of IL‑6R signalling in macrophages increased their skew‑ ing towards a pro-inflammatory ‘M1 phenotype’ in mice that were fed a HFD. Notably, such differences were not seen in mice that were maintained on a normal chow diet. Additional experiments showed that IL‑6 promotes an alternatively activated ‘M2 phenotype’ in macro phages by upregulating the expression of the IL‑4R. IL‑6 induced IL‑4R expression in macrophages in a signal transducer and activator of transcrip‑ tion 3 (STAT3)-dependent manner; as such, IL‑6 promoted IL‑4R signal‑ ling and augmented IL‑4‑mediated STAT6 phosphorylation. In line with these findings, the authors found that IL‑4 treatment improved glucose tolerance in wild-type animals on a HFD, but was less effective in preventing the development of insulin resistance in Il6raΔmyel mice that were fed a HFD. Finally, they found that IL‑6R signalling limits the expression of pro-inflammatory genes in lipopolysaccharide (LPS)stimulated macrophages and showed that Il6raΔmyel mice were more sensitive to LPS-induced endotoxaemia than control mice. The authors conclude that the increased production of IL‑6 that occurs during obesity skews macro phages towards a less inflammatory M2 phenotype, thereby limiting the development of insulin resistance. It will be interesting to examine whether similar beneficial effects of IL‑6 are seen in the setting of human obesity. Yvonne Bordon ORIGINAL RESEARCH PAPER Mauer, J. et al. Signaling by IL‑6 promotes alternative activation of macrophages to limit endotoxemia and obesityassociated resistance to insulin. Nature Immunol. http://dx.doi.org/10.1038/ni.2865 (2014)
VOLUME 14 | MAY 2014 © 2014 Macmillan Publishers Limited. All rights reserved
