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

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105 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

Cite this

Kraakman, M. J., Kammoun, H. L., Allen, T. L., Deswaerte, V., Henstridge, D. C., Estevez, E., Matthews, V. B., Neill, B. A., White, D. A., Murphy, A. J., Peijs, L., Yang, C., Risis, S., Bruce, C. R., Du, X-J., Bobik, A., Lee-Young, R. S., Kingwell, B. A., Vasanthakumar, A., ... Febbraio, M. A. (2015). Blocking IL-6 trans-signaling prevents high-fat diet-induced adipose tissue macrophage recruitment but does not improve insulin resistance. Cell Metabolism, 21(3), 403-416. https://doi.org/10.1016/j.cmet.2015.02.006