Blocking IL-6 trans-Signaling Prevents High-Fat Diet-Induced Adipose Tissue Macrophage Recruitment but Does Not Improve Insulin Resistance
Blocking IL-6 trans-Signaling Prevents High-Fat Diet-Induced Adipose Tissue Macrophage Recruitment but Does Not Improve Insulin Resistance
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DOI：
10.1016/j.cmet.2015.02.006
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发表时间：
2015-03-03
期刊：
影响因子：
29
通讯作者：
Febbraio, Mark A.
中科院分区：
文献类型：
--
作者：
Kraakman, Michael J.;Kammoun, Helene L.;Febbraio, Mark A.
白细胞介素-6（IL-6）在炎症和代谢中起着矛盾的作用。IL-6的促炎作用是通过IL-6“反式信号传导”介导的，这是一个可溶性形式的IL-6受体（sIL-6 R）结合IL-6并激活表达gp 130但不表达IL-6受体的炎性细胞中的信号传导的过程。在这里，我们表明，反式信号招募巨噬细胞进入脂肪组织（ATM）。此外，用可溶性gp 130 Fc蛋白阻断反式信号传导可防止高脂饮食（HFD）诱导的ATM积累，但不能改善胰岛素作用。然而，重要的是，与完全消除IL-6信号传导不同，阻断IL-6信号传导不会加剧肥胖诱导的体重增加、肝脏脂肪变性或胰岛素抵抗。我们的数据确定了sIL-6 R作为ATM募集的关键趋化信号，并表明与完全阻断IL-6作用并对代谢稳态产生负面影响的当前治疗相比，选择性阻断IL-6反式信号转导可能是炎症性疾病更有利的治疗选择。
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 transsignaling, 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.