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 have delineated the role of Toll-like receptor 4 (TLR4) signaling and identified a unique role for interferon regulatory factor 3 (IRF3) in alcohol-related inflammation and hepatocyte damage. We reported that the endoplasmic reticulum (ER) adapter, stimulator of interferon genes (STING), is required for IRF3 phosphorylation and thatIRF3, through its BH3 domain, induces mitochondrial apoptosis in hepatocytes. 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 are exploring whether STING activation is at the crossroads of alcohol-induced liver pathology and in addition to ER stress, STING is also activated via cGAS-cGAMP in ALD.
