XBP1-mediated activation of the STING signalling pathway in macrophages contributes to liver fibrosis progression

作者：Qi Wang, Qingfa Bu, Mu Liu, Rui Zhang, Jian Gu, Lei Li, Jinren Zhou, Yuan Liang, Wantong Su, Zheng Liu, Mingming Wang, Zhe-Xiong Lian, Ling Lü, Haoming Zhou · 发表于：JHEP Reports · 年份：2022 · DOI：10.1016/j.jhepr.2022.100555 · 被引用次数：110 · 研究领域：interferon and immune responses、Endoplasmic Reticulum Stress and Disease、Inflammasome and immune disorders

Background & Aims XBP1 modulates the macrophage proinflammatory response, but its function in macrophage stimulator of interferon genes (STING) activation and liver fibrosis is unknown. X-box binding protein 1 (XBP1) has been shown to promote macrophage nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 (NLRP3) activation in steatohepatitis. Herein, we aimed to explore the underlying mechanism of XBP1 in the regulation of STING signalling and the subsequent NLRP3 activation during liver fibrosis. Methods XBP1 expression was measured in the human fibrotic liver tissue samples. Liver fibrosis was induced in myeloid-specific Xbp1 -, STING-, and Nlrp3 -deficient mice by carbon tetrachloride injection, bile duct ligation, or a methionine/choline-deficient diet. Results Although increased XBP1 expression was observed in the fibrotic liver macrophages of mice and clinical patients, myeloid-specific Xbp1 deficiency or pharmacological inhibition of XBP1 protected the liver against fibrosis. Furthermore, it inhibited macrophage NLPR3 activation in a STING/IRF3-dependent manner. Oxidative mitochondrial injury facilitated cytosolic leakage of macrophage self-mtDNA and cGAS/STING/NLRP3 signalling activation to promote liver fibrosis. Mechanistically, RNA sequencing analysis indicated a decreased mtDNA expression and an increased BCL2/adenovirus E1B interacting protein 3 (BNIP3)-mediated mitophagy activation in Xbp1 -deficient macrophages. Chromati...