未经证实:XBP1调节巨噬细胞促炎反应,但其在巨噬细胞刺激因子干扰素基因(STING)激活和肝纤维化中的作用尚不清楚。X-box结合蛋白1(XBP1)已被证明可促进巨噬细胞核苷酸结合寡聚化结构域,脂肪性肝炎中富含亮氨酸的重复序列和含pyrin结构域3(NLRP3)的激活。在这里,我们旨在探讨XBP1在STING信号调节和随后的NLRP3激活肝纤维化过程中的潜在机制。
未经证实:在人纤维化肝组织样品中测量XBP1表达。在骨髓特异性Xbp1-中诱导肝纤维化,发抖-,和Nlrp3缺陷小鼠通过四氯化碳注射,胆管结扎,或蛋氨酸/胆碱缺乏的饮食。
UASSIGNED:尽管在小鼠和临床患者的纤维化肝巨噬细胞中观察到XBP1表达增加,骨髓特异性Xbp1缺乏或XBP1的药理抑制保护肝脏免受纤维化。此外,它以STING/IRF3依赖性方式抑制巨噬细胞NLPR3激活。氧化性线粒体损伤促进巨噬细胞自身mtDNA和cGAS/STING/NLRP3信号激活的胞浆渗漏以促进肝纤维化。机械上,RNA测序分析表明,在Xbp1缺陷型巨噬细胞中,mtDNA表达降低,BCL2/腺病毒E1B相互作用蛋白3(BNIP3)介导的线粒体自噬激活增加。染色质免疫沉淀(ChIP)分析进一步表明,剪接的XBP1直接与Bnip3启动子结合,并抑制巨噬细胞中Bnip3的转录。Xbp1缺乏通过促进巨噬细胞中BNIP3介导的线粒体自噬激活来降低mtDNA胞质释放和STING/NLRP3激活,被Bnip3击倒而废除。此外,巨噬细胞XBP1/STING信号传导有助于肝星状细胞的激活。
UNASSIGNED:我们的研究结果表明,XBP1通过BNIP3介导的线粒体自噬调节巨噬细胞自身mtDNA胞质渗漏来控制巨噬细胞cGAS/STING/NLRP3的激活,从而提供了一种新的抗肝纤维化靶点。
UNASSIGNED:肝纤维化是慢性肝病的典型进展过程,由炎症和免疫反应驱动,其特征在于肝脏中的细胞外基质过量。目前,目前尚无有效的肝纤维化治疗策略,导致全世界的高死亡率。在这项研究中,我们发现髓系特异性Xbp1缺乏保护小鼠肝脏免受纤维化,而XBP1抑制改善小鼠肝纤维化。这项研究得出结论,在巨噬细胞中靶向XBP1信号可能提供一种保护肝脏免受纤维化的新策略。
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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. Chromatin immunoprecipitation (ChIP) assays further suggested that spliced XBP1 bound directly to the Bnip3 promoter and inhibited the transcription of Bnip3 in macrophages. Xbp1 deficiency decreased the mtDNA cytosolic release and STING/NLRP3 activation by promoting BNIP3-mediated mitophagy activation in macrophages, which was abrogated by Bnip3 knockdown. Moreover, macrophage XBP1/STING signalling contributed to the activation of hepatic stellate cells.
UNASSIGNED: 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.
UNASSIGNED: Liver fibrosis is a typical progressive process of chronic liver disease, driven by inflammatory and immune responses, and is characterised by an excess of extracellular matrix in the liver. Currently, there is no effective therapeutic strategy for the treatment of liver fibrosis, resulting in high mortality worldwide. In this study, we found that myeloid-specific Xbp1 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.