STING signaling sensing of DRP1-dependent mtDNA release in kupffer cells contributes to lipopolysaccharide-induced liver injury in mice.
STING signaling sensing of DRP1-dependent mtDNA release in kupffer cells contributes to lipopolysaccharide-induced liver injury in mice.
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STING 信号传感枯否细胞中 DRP1 依赖性 mtDNA 释放导致脂多糖诱导的小鼠肝损伤
DOI：
10.1016/j.redox.2022.102367
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发表时间：
2022-08
期刊：
影响因子：
11.4
通讯作者：
Huang, Qiaobing
中科院分区：
文献类型：
--
作者：
Zhang, Qin;Wei, Jiayi;Liu, Zhuanhua;Huang, Xiaoxia;Sun, Maomao;Lai, Wujiang;Chen, Zhenfeng;Wu, Jie;Chen, Yanjia;Guo, Xiaohua;Huang, Qiaobing
枯否细胞（KCs）的异常促炎性激活强烈参与脓毒性肝损伤的发病机制。最近的证据表明，在脓毒症的关键作用，过度刺激因子干扰素基因（STING）信号激活。然而，STING信号在脓毒性肝损伤中的作用仍不清楚。在这项研究中，我们证明了STING信号在脂多糖（LPS）处理后从野生型小鼠分离的KC中被显著激活。STING缺乏有效地保护了LPS处理的小鼠的肝功能，减轻了全身炎症反应并降低了死亡率，STING激动剂（DMXAA）加重了这些反应。重要的是，KCs中的STING信号激活通过促进肝细胞死亡而促进LPS诱导的肝损伤。从机制上讲，STING信号可以通过LPS处理的KC中动力蛋白相关蛋白1（DRP 1）依赖性线粒体分裂释放线粒体DNA（mtDNA）来激活。此外，LPS刺激增强了DRP 1依赖的线粒体ROS产生，这促进了线粒体DNA泄漏到胞质溶胶中以及随后的KCs中的STING信号激活。体内实验表明，Mdivi-1对DRP 1的药理学抑制部分阻止了从LPS攻击的小鼠分离的KC中STING信号的激活，以及减轻肝损伤和抑制全身炎症反应。综上所述，我们的研究全面证实STING信号感知KCs中依赖DRP 1的mtDNA释放，其激活可能在LPS诱导的肝损伤中发挥关键作用，为脓毒性肝损伤的治疗提供了新的视角和治疗靶点。STING信号传导在LPS诱导的脓毒症小鼠的枯否细胞中被激活。枯否细胞中的STING活化促进脓毒症期间的肝细胞死亡。DRP 1依赖的mtDNA释放激活LPS处理的Kupffer细胞中的STING。依赖于DRP 1的线粒体ROS增强了mtDNA的泄漏和随后的STING激活。Mdivi-1减弱库普弗细胞中LPS诱导的STING活化并保护肝功能。
Aberrant pro-inflammatory activation of Kupffer cells (KCs) is strongly involved in the pathogenesis of septic liver injury. Recent evidence indicates the crucial roles of excessive stimulator of interferon genes (STING) signaling activation during sepsis. However, the role of STING signaling in septic liver injury remains unclear. In this study, we demonstrated that STING signaling was markedly activated in KCs isolated from wild type mice after lipopolysaccharide (LPS) treatment. STING deficiency effectively protected liver function, attenuated systemic inflammatory response and decreased mortality in LPS-treated mice, which were aggravated by STING agonist (DMXAA). Importantly, STING signaling activation in KCs contributed to LPS-induced liver injury through promoting hepatocyte death. Mechanistically, STING signaling could be activated by release of mitochondrial DNA (mtDNA) through dynamin-related protein 1 (DRP1)-dependent mitochondrial fission in LPS-treated KCs. Additionally, LPS stimulation enhanced DRP1-dependent mitochondrial ROS production, which promoted the leak of mtDNA into the cytosol and subsequent STING signaling activation in KCs. The in vivo experiments showed that pharmacological inhibition of DRP1 with Mdivi-1 partially prevented the activation of STING signaling in KCs isolated from LPS-challenged mice, as well as alleviated liver injury and inhibited systemic inflammatory response. In summary, our study comprehensively confirmed that STING signaling senses the DRP1-dependent release of mtDNA in KCs and its activation might play a key role in LPS-induced liver injury, which offers new sights and therapeutic targets for management of septic liver injury. STING signaling is activated in Kupffer cells in LPS-induced septic mice. STING activation in Kupffer cells promotes hepatocyte death during sepsis. DRP1-dependent mtDNA release activates STING in LPS-treated Kupffer cells. DRP1-dependent mtROS enhances the leak of mtDNA and the subsequent STING activation. Mdivi-1 attenuates LPS-induced STING activation in Kupffer cells and protects liver function.
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DOI：
10.1038/s41577-021-00524-z
发表时间：
2021-09
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Decout A;Katz JD;Venkatraman S;Ablasser A
通讯作者：
Ablasser A
DOI：
10.1016/j.jbc.2021.100904
发表时间：
2021-07
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Wang Y;Li N;Zhang X;Horng T
通讯作者：
Horng T
Mdivi-1 通过独立于 Drp1 GTPase 活性的机制减轻氧化应激并在缺血/缺氧损伤中发挥血管保护作用
影响因子：
11.4
作者：
Duan, Chenyang;Wang, Li;Li, Tao
通讯作者：
Li, Tao
影响因子：
56.9
作者：
McArthur, Kate;Whitehead, Lachlan W.;Kile, Benjamin T.
通讯作者：
Kile, Benjamin T.
DOI：
10.1186/s13054-020-03327-1
发表时间：
2020-10-19
期刊：
Critical care (London, England)
影响因子：
--
作者：
Sun J;Zhang J;Wang X;Ji F;Ronco C;Tian J;Yin Y
通讯作者：
Yin Y