Downregulation of macrophage Irs2 by hyperinsulinemia impairs IL-4-indeuced M2a-subtype macrophage activation in obesity.
Downregulation of macrophage Irs2 by hyperinsulinemia impairs IL-4-indeuced M2a-subtype macrophage activation in obesity.
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DOI：
10.1038/s41467-018-07358-9
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发表时间：
2018-11-19
影响因子：
16.6
通讯作者：
Kadowaki T
中科院分区：
文献类型：
--
作者：
Kubota T;Inoue M;Kubota N;Takamoto I;Mineyama T;Iwayama K;Tokuyama K;Moroi M;Ueki K;Yamauchi T;Kadowaki T
已知M2 a亚型巨噬细胞活化在肥胖症中受损，但其潜在机制仍知之甚少。在此，我们证明，IL-4/Irs 2/Akt通路选择性受损，沿着巨噬细胞Irs 2表达降低，尽管IL-4/STAT 6通路得以维持。事实上，骨髓细胞特异性Irs 2缺陷小鼠显示IL-4诱导的M2 a亚型巨噬细胞活化受损，这是FoxO 1/HDAC 3/NCoR 1辅阻遏物复合物稳定的结果，导致HF饮食条件下的胰岛素抵抗。此外，巨噬细胞Irs 2表达的减少由高胰岛素血症通过胰岛素受体（IR）介导。在骨髓细胞特异性IR缺陷小鼠中，IL-4/Irs 2途径在巨噬细胞中保留，这导致胰岛素抵抗程度降低，因为缺乏IR介导的Irs 2下调。我们的结论是，高胰岛素血症引起的巨噬细胞Irs 2的下调是通过损害肥胖症中M2 a亚型巨噬细胞活化而导致全身性胰岛素抵抗的原因。肥胖与低度慢性炎症有关。在这里，作者表明抗炎M2 a亚型巨噬细胞的激活需要IL 4/Irs 2/Akt途径。由于Irs 2表达减少，该途径在肥胖小鼠中受损，从而导致M2 a活化缺陷。
M2a-subtype macrophage activation is known to be impaired in obesity, although the underlying mechanisms remain poorly understood. Herein, we demonstrate that, the IL-4/Irs2/Akt pathway is selectively impaired, along with decreased macrophage Irs2 expression, although IL-4/STAT6 pathway is maintained. Indeed, myeloid cell-specific Irs2-deficient mice show impairment of IL-4-induced M2a-subtype macrophage activation, as a result of stabilization of the FoxO1/HDAC3/NCoR1 corepressor complex, resulting in insulin resistance under the HF diet condition. Moreover, the reduction of macrophage Irs2 expression is mediated by hyperinsulinemia via the insulin receptor (IR). In myeloid cell-specific IR-deficient mice, the IL-4/Irs2 pathway is preserved in the macrophages, which results in a reduced degree of insulin resistance, because of the lack of IR-mediated downregulation of Irs2. We conclude that downregulation of Irs2 in macrophages caused by hyperinsulinemia is responsible for systemic insulin resistance via impairment of M2a-subtype macrophage activation in obesity. Obesity is associated with low-grade chronic inflammation. Here the authors show that the activation of anti-inflammatory M2a-subtype macrophages requires the IL4/Irs2/Akt pathway. Due to decreased Irs2 expression this pathway is impaired in obese mice thus leading to a defect in M2a activation.
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影响因子：
82.9
作者：
Arkan, MC;Hevener, AL;Karin, M
通讯作者：
Karin, M
影响因子：
7.7
作者：
Kawano Y;Nakae J;Watanabe N;Fujisaka S;Iskandar K;Sekioka R;Hayashi Y;Tobe K;Kasuga M;Noda T;Yoshimura A;Onodera M;Itoh H
通讯作者：
Itoh H
影响因子：
3
作者：
Clausen, BE;Burkhardt, C;Förster, I
通讯作者：
Förster, I
DOI：
10.1152/ajpgi.00391.2009
发表时间：
2010-01-01
影响因子：
4.5
作者：
Lanthier, Nicolas;Molendi-Coste, Olivier;Leclercq, Isabelle A.
通讯作者：
Leclercq, Isabelle A.
巨噬细胞靶向疗法：基于CD64的免疫毒素，用于治疗慢性炎性疾病。
影响因子：
4.2
作者：
Hristodorov D;Mladenov R;Huhn M;Barth S;Thepen T
通讯作者：
Thepen T