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

Abstract

Abstract 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 the ConA-induced liver damage, 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, 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 accelerate ConA-induced acute liver injury, and its mechanism might be related to facilitating leukocyte chemotaxis and promoting liver inflammatory response.