TY - JOUR
T1 - Blocking IL-6 trans-signaling prevents high-fat diet-induced adipose tissue macrophage recruitment but does not improve insulin resistance
AU - Kraakman, Michael J.
AU - Kammoun, Helene L.
AU - Allen, Tamara L
AU - Deswaerte, Virginie
AU - Henstridge, Darren C.
AU - Estevez, Emma
AU - Matthews, Vance B
AU - Neill, Bronwyn A
AU - White, David A.
AU - Murphy, Andrew J.
AU - Peijs, Lone
AU - Yang, Christine
AU - Risis, Steve
AU - Bruce, Clinton R.
AU - Du, Xiao-Jun
AU - Bobik, Alex
AU - Lee-Young, Robert S.
AU - Kingwell, Bronwyn A.
AU - Vasanthakumar, Ajithkumar
AU - Shi, Wei
AU - Kallies, Axel
AU - Lancaster, Graeme I.
AU - Rose-John, Stefan
AU - Febbraio, Mark A.
PY - 2015/3/3
Y1 - 2015/3/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84924415012&partnerID=8YFLogxK
U2 - 10.1016/j.cmet.2015.02.006
DO - 10.1016/j.cmet.2015.02.006
M3 - Article
AN - SCOPUS:84924415012
SN - 1550-4131
VL - 21
SP - 403
EP - 416
JO - Cell Metabolism
JF - Cell Metabolism
IS - 3
ER -
