STING-IRF3 Triggers Endothelial Inflammation in Response to Free Fatty Acid-Induced Mitochondrial Damage in Diet-Induced Obesity.
STING-IRF3 Triggers Endothelial Inflammation in Response to Free Fatty Acid-Induced Mitochondrial Damage in Diet-Induced Obesity.
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DOI：
10.1161/atvbaha.117.309017
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发表时间：
2017-05
期刊：
影响因子：
--
通讯作者：
Shen YH
中科院分区：
文献类型：
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作者：
Mao Y;Luo W;Zhang L;Wu W;Yuan L;Xu H;Song J;Fujiwara K;Abe JI;LeMaire SA;Wang XL;Shen YH
肥胖中的代谢应激会诱发内皮炎症和激活，从而引发脂肪组织炎症、胰岛素抵抗和心血管疾病。然而，内皮炎症诱导的机制尚不完全清楚。干扰素基因刺激物（STING）是免疫和炎症中的重要分子。在本研究中，我们试图确定 STING 在棕榈酸 (PA) 诱导的内皮激活/炎症中的作用。在培养的内皮细胞中，PA 处理激活了 STING，其核周易位和与干扰素调节因子 3 (IRF3) 的结合表明，导致 IRF3 磷酸化和核易位。激活的IRF3与细胞间粘附分子1（ICAM-1）的启动子结合并诱导ICAM-1表达和单核细胞-内皮细胞粘附。在分析上游信号时，我们发现 PA 通过诱导线粒体损伤来激活 STING。 PA 处理导致线粒体损伤和线粒体 DNA (mtDNA) 渗漏到细胞质中。通过胞质 DNA 传感器环 GMP-AMP 合酶 (cGAS)，线粒体损伤和泄漏的胞质 mtDNA 激活了 STING-IRF3 通路并增加了 ICAM-1 的表达。在饮食诱导的肥胖小鼠中，脂肪组织中的 STING-IRF3 通路被激活。然而，STING 缺陷 (Stinggt/gt) 部分预防了饮食引起的脂肪组织炎症、肥胖、胰岛素抵抗和葡萄糖耐受不良。线粒体损伤-cGAS-STING-IRF3 通路在代谢应激诱导的内皮炎症中发挥着重要作用。 STING 可能是预防肥胖个体心血管疾病和胰岛素抵抗的潜在治疗靶点。
Metabolic stress in obesity induces endothelial inflammation and activation, which initiates adipose tissue inflammation, insulin resistance, and cardiovascular diseases. However, the mechanisms underlying endothelial inflammation induction are not completely understood. Stimulator of interferon genes (STING) is an important molecule in immunity and inflammation. In the present study, we sought to determine the role of STING in palmitic acid (PA)-induced endothelial activation/inflammation. In cultured endothelial cells, PA treatment activated STING, as indicated by its perinuclear translocation and binding to interferon regulatory factor 3 (IRF3), leading to IRF3 phosphorylation and nuclear translocation. The activated IRF3 bound to the promoter of intercellular adhesion molecule 1 (ICAM-1) and induced ICAM-1 expression and monocyte–endothelial cell adhesion. When analyzing the upstream signaling, we found that PA activated STING by inducing mitochondrial damage. PA treatment caused mitochondrial damage and leakage of mitochondrial DNA (mtDNA) into the cytosol. Through the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS), the mitochondrial damage and leaked cytosolic mtDNA activated the STING-IRF3 pathway and increased ICAM-1 expression. In mice with diet-induced obesity, the STING-IRF3 pathway was activated in adipose tissue. However, STING deficiency (Stinggt/gt) partially prevented diet-induced adipose tissue inflammation, obesity, insulin resistance, and glucose intolerance. The mitochondrial damage-cGAS-STING-IRF3 pathway is critically involved in metabolic stress-induced endothelial inflammation. STING may be a potential therapeutic target for preventing cardiovascular diseases and insulin resistance in obese individuals.