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