1. Academic Validation
  2. 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

  • Redox Biol. 2022 Aug;54:102367. doi: 10.1016/j.redox.2022.102367.
Qin Zhang 1 Jiayi Wei 1 Zhuanhua Liu 1 Xiaoxia Huang 1 Maomao Sun 1 Wujiang Lai 2 Zhenfeng Chen 1 Jie Wu 3 Yanjia Chen 4 Xiaohua Guo 1 Qiaobing Huang 5
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Shock and Microcirculation, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.
  • 2 Department of Gynecology, Obstetrics and Gynecology Center, Zhujiang Hospital, Southern Medical University, Guangzhou, 510515, China.
  • 3 Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
  • 4 Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
  • 5 Guangdong Provincial Key Laboratory of Shock and Microcirculation, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China; Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. Electronic address: bing@smu.edu.cn.
Abstract

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.

Keywords

DRP1; Kupffer cell; LPS; Liver injury; STING; mtDNA.

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