Deletion of Cyclic GMP-AMP Synthase Aggravates Concanavalin A-Induced Acute Hepatic Injury by Facilitating Leukocyte Chemotaxis

趋化性 肝损伤 刀豆蛋白A 基因敲除 生物 炎症 肝细胞 免疫系统 先天免疫系统 免疫学 下调和上调 脂多糖 分子生物学 细胞凋亡 内分泌学 基因 生物化学 体外 受体
作者
Jiaxin Liu,Shuang Ji,Zhaiyi Liu,Meina Guo,Guangrui Yang,Lihong Chen
出处
期刊:Inflammation [Springer Nature]
卷期号:46 (3): 1118-1130 被引量:1
标识
DOI:10.1007/s10753-023-01798-2
摘要

Growing evidence demonstrates that cyclic GMP-AMP synthase (cGAS), as a cytosolic DNA sensor, is essential for activating innate immunity and regulating inflammatory response against cellular damage. However, its role in immune-mediated hepatitis remains unclear. Here by challenging the cGAS knockout (KO) and their littermate wide-type (WT) mice with intravenous ConA injection to induce acute immune-mediated liver injury, we found that lack of cGAS drastically aggravated liver damage post ConA treatment for 24 h, reflected by increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and amplified hepatic necrosis. The number of apoptotic hepatocytes was also significantly increased in the KO mice. RNA-sequencing analysis revealed that leukocyte chemotaxis and migration-related genes were remarkably upregulated in the KO livers. Consistently, immunofluorescence assays illustrated that the infiltrating F4/80-positive macrophages, Ly6G-positive neutrophils, and CD3-positive T cells were all significantly increased in the KO liver sections. The hepatic expression of the pro-inflammatory genes was elevated as well. Supporting the in vivo findings, the knockdown of cGAS in cultured macrophages showed promoted migration potential and enhanced pro-inflammatory gene expression. These results collectively demonstrated that deletion of cGAS could aggravate ConA-induced acute liver injury, at least at the 24-h time point, and its mechanism might be related to facilitating leukocyte chemotaxis and promoting liver inflammatory response.
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