STING signaling sensing of DRP1-dependent mtDNA release in kupffer cells contributes to lipopolysaccharide-induced liver injury in mice

• Published in: Redox biology Vol. 54; p. 102367
• Main Authors: Zhang, Qin, Wei, Jiayi, Liu, Zhuanhua, Huang, Xiaoxia, Sun, Maomao, Lai, Wujiang, Chen, Zhenfeng, Wu, Jie, Chen, Yanjia, Guo, Xiaohua, Huang, Qiaobing
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.08.2022; Elsevier
• Subjects: Animals; Chemical and Drug Induced Liver Injury, Chronic - metabolism; DNA, Mitochondrial - genetics; DNA, Mitochondrial - metabolism; DRP1; Dynamins - genetics; Dynamins - metabolism; Kupffer cell; Kupffer Cells - metabolism; Lipopolysaccharides - toxicity; Liver injury; LPS; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; mtDNA; Research Paper; Sepsis - genetics; Sepsis - metabolism; STING; Kupffer cell; STING; mtDNA; LPS; DRP1; Liver injury
• ISSN: 2213-2317; 2213-2317
• DOI: 10.1016/j.redox.2022.102367

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. [Display omitted] •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.