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

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

Research output: Contribution to journalArticleResearchpeer-review

121 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)403-416
Number of pages14
JournalCell Metabolism
Volume21
Issue number3
DOIs
Publication statusPublished - 3 Mar 2015
Externally publishedYes

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