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

Abstract

Growing evidence demonstrates that cyclic GMP-AMP synthase (cGAS), as a cytosolic DNA sensor, is essential for activating innate immunity and regulating in ammatory 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 immunemediated liver injury, we found that lack of cGAS drastically aggravated the ConA-induced liver damage, re ected by increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and ampli ed hepatic necrosis. The number of apoptotic hepatocytes was also signi cantly increased in the KO mice. RNA-sequencing analysis revealed that leukocyte chemotaxis and migration related genes were remarkably upregulated in the KO livers. Consistently, immuno uorescence assays illustrated that the in ltrating F4/80-positive macrophages, Ly6G-positive neutrophils, and CD3-positive T cells were all signi cantly increased in the KO liver sections. The hepatic expression of the pro-in ammatory genes was elevated as well. Supporting the in vivo ndings, knockdown of cGAS in cultured macrophages showed promoted migration potential and enhanced pro-in ammatory gene expression. These results collectively demonstrated that deletion of cGAS could accelerate ConA-induced acute liver injury, and its mechanism might be related to facilitating leukocyte chemotaxis and promoting liver in ammatory response.