Xu Jian, Wu Dongming, Zhou Shun, Hu Haoran, Li Fei, Guan Zhu, Zhan Xinyu, Gao Yiyun, Wang Ping, Rao Zhuqing
Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, 210029, Nanjing, China.
Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, 210029, Nanjing, China.
Cell Death Discov. 2023 Feb 10;9(1):58. doi: 10.1038/s41420-023-01357-6.
Mixed-lineage kinase domain-like protein (MLKL)-mediated necroptosis has been implicated in aggravating liver ischemia and reperfusion (IR) injury. However, the precise role and mechanism of MLKL in regulating oxidative DNA damage of hepatocytes and subsequent activation of macrophage stimulator of interferon genes (STING) signaling remains unclear. In this study, we investigated the role of MLKL in regulating the interplay between hepatocyte injury and macrophage pro-inflammatory responses during liver IR injury. We found that IR increased MLKL expression in liver tissues of wild type (WT) mice. MLKL knockout (KO) attenuated liver IR injury and suppressed the activation of cGAS-STING signaling in intrahepatic macrophages, which was abrogated by STING activation with its agonist. Mechanistically, IR induced oxidative DNA damage in hepatocytes, leading to cGAS-STING activation in macrophages, which was suppressed by MLKL KO. Moreover, increased PTEN-induced kinase 1 (PINK1)-mediated mitophagy contributed to reduced oxidative DNA damage in hepatocytes and subsequent decreased activation of STING signaling in macrophages in MLKL KO mice. Our findings demonstrated a non-canonical role of MLKL in the pathogenesis of liver IR. MLKL deficiency significantly promoted PINK1-mediated mitophagy activation to inhibit oxidative DNA damage in hepatocytes, which in turn suppressed macrophage cGAS-STING activation and inflammatory liver IR injury.
混合谱系激酶结构域样蛋白（MLKL）介导的坏死性凋亡与加重肝脏缺血再灌注（IR）损伤有关。然而，MLKL在调节肝细胞氧化DNA损伤以及随后激活干扰素基因刺激物（STING）信号通路中的具体作用和机制仍不清楚。在本研究中，我们探讨了MLKL在肝脏IR损伤期间调节肝细胞损伤与巨噬细胞促炎反应之间相互作用中的作用。我们发现，IR增加了野生型（WT）小鼠肝脏组织中MLKL的表达。MLKL基因敲除（KO）减轻了肝脏IR损伤，并抑制了肝内巨噬细胞中cGAS-STING信号通路的激活，而STING激动剂激活STING可消除这种抑制作用。机制上，IR诱导肝细胞发生氧化DNA损伤，导致巨噬细胞中cGAS-STING激活，而MLKL基因敲除可抑制这种激活。此外，在MLKL基因敲除小鼠中，PTEN诱导激酶1（PINK1）介导的线粒体自噬增加，有助于减少肝细胞中的氧化DNA损伤，并随后降低巨噬细胞中STING信号通路的激活。我们的研究结果证明了MLKL在肝脏IR发病机制中的非经典作用。MLKL缺乏显著促进PINK1介导的线粒体自噬激活，以抑制肝细胞中的氧化DNA损伤，进而抑制巨噬细胞cGAS-STING激活和炎症性肝脏IR损伤。
