Blocking IL-6 trans-Signaling Prevents High-Fat Diet-Induced Adipose Tissue Macrophage Recruitment but Does Not Improve Insulin Resistance Academic Article uri icon

abstract

  • 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.

authors

  • Kraakman, Michael J
  • Kammoun, Helene L
  • Allen, Tamara L
  • Deswaerte, Virginie
  • Henstridge, Darren C
  • Estevez, Emma
  • Matthews, Vance B
  • Neill, Bronwyn
  • White, David A
  • Murphy, Andrew J
  • Peijs, Lone
  • Yang, Christine
  • Risis, Steve
  • Bruce, Clinton R
  • Du, Xiao-Jun
  • Bobik, Alex
  • Lee-Young, Robert S
  • Kingwell, Bronwyn A
  • Vasanthakumar, Ajithkumar
  • Shi, Wei
  • Kallies, Axel
  • Lancaster, Graeme I
  • Rose-John, Stefan
  • Febbraio, Mark A

publication date

  • March 2015