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Blocking IL-6 trans-signaling prevents high-fat diet-induced adipose tissue macrophage recruitment but does not improve insulin resistance
journal contributionposted on 2023-05-20, 04:46 authored by Kraakman, MJ, Kammoun, HL, Allen, TL, Deswaerte, V, Darren HenstridgeDarren Henstridge, Estevez, E, Matthews, VB, Neill, B, White, DA, Murphy, AJ, Peijs, L, Yang, C, Risis, S, Bruce, CR, Du, X-J, Bobik, A, Lee-Young, RS, Kingwell, BA, Vasanthakumar, A, Shi, W, Kallies, A, Lancaster, GI, Rose-John, S, Febbraio, MA
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.
Publication titleCell Metabolism
Department/SchoolSchool of Health Sciences
Place of publicationUnited States
Rights statementCopyright 2015 Elsevier Inc.