Cyclic GMP–AMP synthase deficiency predisposes the liver to alcohol-induced cell death and ER stress

Background: Cyclic GMP–AMP synthase (cGAS) catalyzes the production of cGAMP, which activates the STING–IRF3 signaling pathway. Previous investigations indicated a role for STING–IRF3 in early alcohol-associated liver disease (ALD). In this study, we examined the role of cGAS in liver damage and inflammation in early ALD. Methods: Wild-type (WT) or cGAS knockout (cGAS-KO) mice received a single dose of alcohol (5 g/kg), and in WT mice with or without a cGAS inhibitor, RU.521 (5 mg/kg) or 2′–3′ cGAMP or control. Liver and serum were evaluated after 9 hours of alcohol administration. Results: Alcohol gavage in cGAS knockout (cGAS-KO) mice led to increased liver damage compared with WT mice. Inhibition of cGAS with the small molecule, RU.521, also resulted in increased serum alanine and aspartate aminotransferases. cGAS deficiency or inhibition made the liver susceptible to alcohol-induced apoptosis. Alcohol-fed cGAS-KO mice and WT mice treated with the cGAS inhibitor showed enhanced unfolded protein response in the liver. This was associated with elevated levels of the proinflammatory cytokines, macrophage migration inhibitory factor, CD68 + cells, Ly6G + cells, and chemokines like lipocalin-2 and neutrophil elastase. Primary hepatocytes isolated from cGAS-KO mice displayed increased levels of cleaved caspase-3, XBP1s, and CHOP after alcohol administration as compared with WT control hepatocytes. Interestingly, restoration of cGAMP levels after cGAS inhibition improved liver damage and autophagic flux. Conclusions: Our findings highlight that cGAS deficiency or cGAS inhibition predisposes the liver to increased damage, apoptosis, and unfolded protein response in early ALD. An increase in the proinflammatory cytokine MIF and chemokines involved in neutrophil recruitment might contribute to the increased liver damage. In summary, our findings indicate a protective role for cGAS activation in early ALD.