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

著者: 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 - JHEP Reports 2022 被引用: 106

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: -deficient mice by carbon tetrachloride injection, bile duct ligation, or a methionine/choline-deficient diet. Results: knockdown. Moreover, macrophage XBP1/STING signalling contributed to the activation of hepatic stellate cells. Conclusions: Our findings demonstrate that XBP1 controls macrophage cGAS/STING/NLRP3 activation by regulating macrophage self-mtDNA cytosolic leakage via BNIP3-mediated mitophagy modulation, thus providing a novel target against liver fibrosis. Lay summary: deficiency protected the liver against fibrosis in mice, while XBP1 inhibition ameliorated liver fibrosis in mice. This study concluded that targeting XBP1 signalling in macrophages may provide a novel strategy for protecting the liver against fibrosis.