The Third Xiangya Hospital of Central South University, Department of Hepatopancreatobiliary Surgery, 138 Tongzipo Road, Changsha City, Hunan Province, China.
The Third Xiangya Hospital of Central South University, Surgery Center, 138 Tongzipo Road, Changsha City, Hunan Province, China.
Int Immunopharmacol. 2023 Dec;125(Pt B):111132. doi: 10.1016/j.intimp.2023.111132. Epub 2023 Nov 9.
Inflammation plays an essential role in the development liver fibrosis.The Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) is a central cytoplasmic DNA sensor which can recognize cytoplasmic DNA, known to trigger stimulator of interferon genes (STING) and downstream proinflammatory factors. Here, we investigated the role of cGAS-STING signaling pathway in the pathogenesis of liver fibrosis.Differentially expressed genes (DEGs) in human liver tissue were identified using RNA-Seq analysis. As models of liver fibrosis, chronic Carbon tetrachloride (CCl) exposure were applied in cGAS-knockout mice. LX-2 cells were co-cultured with human liver sinusoidal endothelial cells (LSECs) to explore the underlying mechanisms of hepatic sinusoidal microthrombosis in an inflammatory microenvironment. The endoscopic ultrasound-guided portal vein pressure gradient (EUS-PPG) method was used to analyze the associations between hepatic sinusoidal microthrombosis and PPG in patients with liver fibrosis and portal hypertension (PTH). The RNA-seq analysis results showed that DEGs were enriched in inflammation and endothelial cell activation. The upregulation of the cGAS-STING signaling exacerbated liver fibrosis and intrahepatic inflammation. It also exacerbated LSECs impairment and increased the contribution of hepatic sinusoidal microthrombosis to liver fibrosis in vivo and in vitro. Prothrombotic mediators and proinflammatory factors were associated with PPG in patients with liver fibrosis and portal hypertension. Therefore, activating cGAS-STING signaling pathway promotes liver fibrosis and hepatic sinusoidal microthrombosis, which may lead to increased portal vein pressure.
炎症在肝纤维化的发展中起着至关重要的作用。环鸟苷酸-腺苷酸合酶（cGAS）是一种中央细胞质 DNA 传感器，可识别细胞质 DNA，已知其可触发干扰素基因刺激物（STING）和下游促炎因子。在这里，我们研究了 cGAS-STING 信号通路在肝纤维化发病机制中的作用。使用 RNA-Seq 分析鉴定人肝组织中的差异表达基因（DEGs）。作为肝纤维化模型，慢性四氯化碳（CCl）暴露应用于 cGAS 敲除小鼠。LX-2 细胞与人肝窦内皮细胞（LSEC）共培养，以在炎症微环境中探索肝窦微循环血栓形成的潜在机制。内镜超声引导下门静脉压力梯度（EUS-PPG）方法用于分析肝纤维化和门静脉高压（PTH）患者肝窦微循环血栓形成与 PPG 之间的关联。RNA-seq 分析结果表明，DEGs 在炎症和内皮细胞激活中富集。cGAS-STING 信号的上调加剧了肝纤维化和肝内炎症。它还加剧了 LSEC 的损伤，并增加了肝窦微循环血栓形成对体内和体外肝纤维化的贡献。促血栓形成介质和促炎因子与肝纤维化和门静脉高压患者的 PPG 相关。因此，激活 cGAS-STING 信号通路可促进肝纤维化和肝窦微循环血栓形成，从而导致门静脉压力升高。
