[PDF][PDF] Blocking IL-6 trans-signaling prevents high-fat diet-induced adipose tissue macrophage recruitment but does not improve insulin resistance

MJ Kraakman, HL Kammoun, TL Allen, V Deswaerte… - Cell metabolism, 2015 - cell.com
MJ Kraakman, HL Kammoun, TL Allen, V Deswaerte, DC Henstridge, E Estevez
Cell metabolism, 2015cell.com
Summary Interleukin-6 (IL-6) plays a paradoxical role in inflammation and metabolism. The
pro-inflammatory effects of IL-6 are mediated via IL-6" trans-signaling," a process where the
soluble form of the IL-6 receptor (sIL-6R) binds IL-6 and activates signaling in inflammatory
cells that express the gp130 but not the IL-6 receptor. Here we show that trans-signaling
recruits macrophages into adipose tissue (ATM). Moreover, blocking trans-signaling with
soluble gp130Fc protein prevents high-fat diet (HFD)-induced ATM accumulation, but does …
Summary
Interleukin-6 (IL-6) plays a paradoxical role in inflammation and metabolism. The pro-inflammatory effects of IL-6 are mediated via IL-6 "trans-signaling," a process where the soluble form of the IL-6 receptor (sIL-6R) binds IL-6 and activates signaling in inflammatory cells that express the gp130 but not the IL-6 receptor. Here we show that trans-signaling recruits macrophages into adipose tissue (ATM). Moreover, blocking trans-signaling with soluble gp130Fc protein prevents high-fat diet (HFD)-induced ATM accumulation, but does not improve insulin action. Importantly, however, blockade of IL-6 trans-signaling, unlike complete ablation of IL-6 signaling, does not exacerbate obesity-induced weight gain, liver steatosis, or insulin resistance. Our data identify the sIL-6R as a critical chemotactic signal for ATM recruitment and suggest that selectively blocking IL-6 trans-signaling may be a more favorable treatment option for inflammatory diseases, compared with current treatments that completely block the action of IL-6 and negatively impact upon metabolic homeostasis.
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