Innate Immune Signaling

The pathomechanism of alcoholic liver disease (ALD) involves cumulative events such as leaky gut,hepatocyte damage and inflammation that collectively contribute to the severity of disease. Our studies havedelineated the role of Toll-like receptor 4 (TLR4) signaling and identified a unique role for interferon regulatoryfactor 3 (IRF3) in alcohol-related inflammation and hepatocyte damage. We reported that the endoplasmicreticulum (ER) adapter, stimulator of interferon genes (STING), is required for IRF3 phosphorylation and thatIRF3, through its BH3 domain, induces mitochondrial apoptosis in hepatocytes. Our new data show thatalcohol binge or chronic alcohol result in an increase in circulating bacterial 16S DNA and mitochondrial DNAin mice and humans. These double stranded DNAs are ligands for the cyclic GMP-AMP kinase (cGAS) that produces 2′3′-cGAMP (cGAMP) that can activate STING to trigger IRF3 activation and Type I IFN production.
We postulate that STING activation is at the crossroads of alcohol-induced liver pathology and in addition toER stress, STING is also activated via cGAS-cGAMP in ALD. We found that mice deficient in cGAS haveattenuated liver damage after an acute binge or acute-on-chronic alcohol use but not after chronic steady alcohol. Thus, we hypothesize that cGAS-mediated signals and STING activation represent a trigger for an acute-on-chronic alcohol-induced liver injury often seen in acute alcoholic hepatitis. While cGAS is mostly
studied in immune cells, we found that it is also expressed and functional in hepatocytes. Thus, we hypothesize that the cGAS-2′3′-cGAMP-STING activation axis plays a role both in hepatocytes and immunecells in alcoholic hepatitis. We also discovered that sterile danger signals released by damaged hepatocytes activate the NLRP3 inflammasome in immune cells and that disruption of inflammasome activation pathwayscan ameliorate ALD in mice. Recent reports indicate that ER stress is another inducer of inflammasome activation via NLRP3 and involves mitochondrial damage. Based on these key findings, we propose that inflammasome activation in ALD can be triggered not only by sterile danger signals but also by ER stress.