Macrophage CGI-58 deficiency activates ROS-inflammasome pathway to promote insulin resistance in mice.
Macrophage CGI-58 deficiency activates ROS-inflammasome pathway to promote insulin resistance in mice.
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DOI：
10.1016/j.celrep.2014.02.047
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发表时间：
2014-04-10
期刊：
影响因子：
8.8
通讯作者：
Yu L
中科院分区：
文献类型：
--
作者：
Miao H;Ou J;Ma Y;Guo F;Yang Z;Wiggins M;Liu C;Song W;Han X;Wang M;Cao Q;Chung BH;Yang D;Liang H;Xue B;Shi H;Gan L;Yu L
过度营养可激活巨噬细胞的促炎程序，诱导胰岛素抵抗(IR)，但其分子机制尚不完全清楚。在这里，我们显示饱和脂肪酸和脂多糖，这两个与高脂饮食(HFD)诱导的IR有关的因素，抑制巨噬细胞CGI-58的表达。小鼠巨噬细胞特异性CGI-58基因敲除(MAKO)加重了HFD诱导的糖耐量异常和IR，这与全身/组织炎症和脂肪组织巨噬细胞的促炎激活有关。由于过氧化物酶体增殖物激活受体-γ信号通路的缺陷，CGI-58缺陷的巨噬细胞表现出线粒体功能障碍。因此，它们过度产生活性氧(ROS)，通过激活NLRP3炎症小体来促进促炎细胞因子的分泌。抗ROS治疗或NLRP3沉默可防止CGI-58缺陷的巨噬细胞过度分泌促炎细胞因子，并在共培养的脂肪切片中诱导促炎信号和IR。抗ROS治疗还可以防止高脂饲料喂养的Mako小鼠炎症和IR的加剧。因此，我们的数据证实CGI-58是营养过剩诱导的巨噬细胞中NLRP3炎症体激活的抑制因子。
Overnutrition activates proinflammatory program in macrophages to induce insulin resistance (IR), but its molecular mechanisms remain incompletely understood. Here we show that saturated fatty acid and lipopolysaccharide, two factors implicated in high-fat diet (HFD)-induced IR, suppress macrophage CGI-58 expression. Macrophage-specific CGI-58 knockout (MaKO) in mice aggravates HFD-induced glucose intolerance and IR, which is associated with augmented systemic/tissue inflammation and proinflammatory activation of adipose tissue macrophages. CGI-58-deficient macrophages exhibit mitochondrial dysfunction due to defective peroxisome proliferator-activated receptor (PPAR)-γ signaling. Consequently they overproduce reactive oxygen species (ROS) to potentiate secretion of proinflammatory cytokines by activating NLRP3 inflammasome. Anti-ROS treatment or NLRP3 silencing prevents CGI-58-deficient macrophages from over-secreting proinflammatory cytokines and from inducing proinflammatory signaling and IR in the co-cultured fat slices. Anti-ROS treatment also prevents exacerbation of inflammation and IR in HFD-fed MaKO mice. Our data thus establish CGI-58 as a suppressor of overnutrition-induced NLRP3 inflammasome activation in macrophages.
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