XBP1 deficiency promotes hepatocyte pyroptosis by impairing mitophagy to activate mtDNA-cGAS-STING signaling in macrophages during acute liver injury

粒体自噬 上睑下垂 细胞生物学 肝损伤 肝细胞 线粒体ROS 自噬 线粒体 生物 化学 程序性细胞死亡 细胞凋亡 药理学 生物化学 体外
作者
Zheng Liu,Mingming Wang,Xun Wang,Qingfa Bu,Qi Wang,Wantong Su,Lei Li,Ling Lü,Ling Lü
出处
期刊:Redox biology [Elsevier]
卷期号:52: 102305-102305 被引量:138
标识
DOI:10.1016/j.redox.2022.102305
摘要

Hepatocellular cell death and macrophage proinflammatory activation contribute to the pathology of various liver diseases, during which XBP1 plays an important role. However, the function and mechanism of XBP1 in thioacetamide (TAA)-induced acute liver injury (ALI) remains unknown. Here, we investigated the effects of XBP1 inhibition on promoting hepatocellular pyroptosis to activate macrophage STING signaling during ALI. While both TAA- and LPS-induced ALI triggered XBP1 activation in hepatocytes, hepatocyte-specific XBP1 knockout mice exhibited exacerbated ALI with increased hepatocellular pyroptosis and enhanced macrophage STING activation. Mechanistically, mtDNA released from TAA-stressed hepatocytes could be engulfed by macrophages, further inducing macrophage STING activation in a cGAS- and dose-dependent manner. XBP1 deficiency increased ROS production to promote hepatocellular pyroptosis by activating NLRP3/caspase-1/GSDMD signaling, which facilitated the extracellular release of mtDNA. Moreover, impaired mitophagy was found in XBP1 deficient hepatocytes, which was reversed by PINK1 overexpression. Mitophagy restoration also inhibited macrophage STING activation and ALI in XBP1 deficient mice. Activation of XBP1-mediated hepatocellular mitophagy and pyroptosis and macrophage STING signaling pathway were observed in human livers with ALI. Collectively, these findings demonstrate that XBP1 deficiency promotes hepatocyte pyroptosis by impairing mitophagy to activate mtDNA/cGAS/STING signaling of macrophages, providing potential therapeutic targets for ALI.
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