Mitochondrial Damage Causes Inflammation via cGAS-STING Signaling in Acute Kidney Injury
Mitochondrial Damage Causes Inflammation via cGAS-STING Signaling in Acute Kidney Injury
复制标题
线粒体损伤通过cGAS刺痛信号在急性肾损伤中引起炎症
DOI：
10.1016/j.celrep.2019.09.050
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发表时间：
2019-10-29
期刊：
影响因子：
8.8
通讯作者：
Inagi, Reiko
中科院分区：
文献类型：
--
作者：
Maekawa, Hiroshi;Inoue, Tsuyoshi;Inagi, Reiko
急性肾损伤（AKI）以线粒体功能障碍和先天免疫系统激活为特征。干扰素基因（STING）通路的环GMP-AMP合成酶（cGAS）刺激物检测胞质DNA并诱导先天免疫。在这里，我们使用顺铂诱导的AKI和培养的小管细胞的基因工程动物模型来研究线粒体损伤和随后cGAS-STING通路的激活的作用。顺铂诱导mtDNA渗漏到细胞质中（可能通过线粒体外膜中的bcl -2样蛋白4 （BAX）孔），随后激活cGAS-STING通路，从而引发炎症和AKI进展，在sting缺陷小鼠中得到改善。在培养的小管细胞中敲除STING可改善顺铂诱导的炎症反应。mtDNA耗竭和补充研究通过细胞质mtDNA激活cGAS-STING信号支持管状炎症反应。因此，我们得出结论，线粒体功能障碍和随后mtDNAc-GAS-STING通路的激活是肾损伤的关键调节因子。
Acute kidney injury (AKI) is characterized by mitochondrial dysfunction and activation of the innate immune system. The cyclic GMP-AMP synthase (cGAS) stimulator of interferon genes (STING) pathway detects cytosolic DNA and induces innate immunity. Here, we investigate the role of mitochondrial damage and subsequent activation of the cGAS-STING pathway using a genetically engineered animal model of cisplatin-induced AKI and cultured tubular cells. Cisplatin induced mtDNA leakage into the cytosol-probably through BCL-2-like protein 4 (BAX) pores in the mitochondrial outer membrane-in tubules, with subsequent activation of the cGAS-STING pathway, thereby triggering inflammation and AKI progression, which is improved in STING-deficient mice. STING knockdown in cultured tubular cells ameliorates inflammatory responses induced by cisplatin. mtDNA depletion and repletion studies support tubular inflammatory responses via the cGAS-STING signal activation by cytosolic mtDNA. Therefore, we conclude that mitochondrial dysfunction and subsequent activation of the mtDNAc-GAS-STING pathway is a critical regulator of kidney injury.