Adiponectin restrains ILC2 activation by AMPK-mediated feedback inhibition of IL-33 signaling.
Adiponectin restrains ILC2 activation by AMPK-mediated feedback inhibition of IL-33 signaling.
复制标题
脂联素通过AMPK介导的反馈抑制IL-33信号传导来限制ILC2激活。
DOI：
10.1084/jem.20191054
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发表时间：
2021-02-01
期刊：
影响因子：
--
通讯作者：
Liu M
中科院分区：
文献类型：
--
作者：
Wang L;Luo Y;Luo L;Wu D;Ding X;Zheng H;Wu H;Liu B;Yang X;Silva F;Wang C;Zhang X;Zheng X;Chen J;Brigman J;Mandell M;Zhou Z;Liu F;Yang XO;Liu M
王等人。证明 AMPK 是 IL-33 信号传导的下游，反馈抑制 ILC2 中 IL-33 诱导的 NF-κB 激活。这项研究发现，脂联素通过 AMPK 充当 ILC2 的负调节因子，并发挥抗发热作用。 ILC2 存在于脂肪组织中，在调节脂肪生热作用中发挥着关键作用。然而，脂肪驻留 ILC2 激活的机制仍不清楚。在这里，我们发现IL-33是一种有效的ILC2激活剂，在初级ILC2中通过TAK1刺激AMPK Thr172位点的磷酸化，这提供了抑制IL-33诱导的NF-κB激活和IL-13产生的反馈机制。用脂联素或脂联素受体激动剂 (AdipoRon) 治疗 ILC2 可激活 AMPK 并减少 IL-33–NF-κB 信号传导。 AdipoRon 还抑制寒冷诱导的生热基因表达和体内能量消耗。相反，脂联素缺乏增加了 ILC2 分数和激活，导致冷暴露小鼠脂肪组织中生热基因表达上调。 ILC2 缺陷或通过用抗 ST2 中和 IL-33 受体来阻断 ILC2 功能，会减弱脂联素对寒冷诱导的脂肪产热和能量消耗的抑制作用。综上所述，我们的研究表明，脂联素通过 AMPK 介导的 IL-33 信号传导负调节，成为脂肪组织中 ILC2 功能的负调节因子。
Wang et al. demonstrate that AMPK is downstream of IL-33 signaling, and feedback inhibits IL-33–induced activation of NF-κB in ILC2s. This study uncovers that adiponectin via AMPK acts as a negative regulator of ILC2s and exerts an antithermogenic effect. ILC2s are present in adipose tissue and play a critical role in regulating adipose thermogenesis. However, the mechanisms underlying the activation of adipose-resident ILC2s remain poorly defined. Here, we show that IL-33, a potent ILC2 activator, stimulates phosphorylation of AMPK at Thr172 via TAK1 in primary ILC2s, which provides a feedback mechanism to inhibit IL-33–induced NF-κB activation and IL-13 production. Treating ILC2s with adiponectin or an adiponectin receptor agonist (AdipoRon) activated AMPK and decreased IL-33–NF-κB signaling. AdipoRon also suppressed cold-induced thermogenic gene expression and energy expenditure in vivo. In contrast, adiponectin deficiency increased the ILC2 fraction and activation, leading to up-regulated thermogenic gene expression in adipose tissue of cold-exposed mice. ILC2 deficiency or blocking ILC2 function by neutralization of the IL-33 receptor with anti-ST2 diminished the suppressive effect of adiponectin on cold-induced adipose thermogenesis and energy expenditure. Taken together, our study reveals that adiponectin is a negative regulator of ILC2 function in adipose tissue via AMPK-mediated negative regulation of IL-33 signaling.
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