Less severe alcoholic injury in cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS) deficient mice, a possible impact of intracellular DNA recognition

Abstract

Alcohol induces free mitochondrial DNA (mtDNA) in the cytosol that might be recognized by cGAS (a receptor for cytosolic DNA), leading to enhanced inflammation. Here, alcohol was tested in vivo and in vitro (macrophages and hepatocytes) using cGAS-deficient (cGAS−/−) mice.As such, less prominent liver damage and systemic inflammation in alcohol-administered cGAS−/− mice were observed when compared to wild-type (WT) mice, as indicated by liver enzymes, histology, hepatocyte apoptosis, oxidative stress (malondialdehyde) with cytokines in the liver tissue, serum cytokines, and gut permeability (FITC-dextran assay) with the differences in fecal microbiota. Alcohol upregulated cGAS and increased 2′,3’-cGAMP (a second messenger produced by cGAS) in bone marrow-derived macrophages (BMDM) and liver-derived hepatocytes from WT mice, but not in the cells from cGAS−/− mice. Meanwhile, alcohol induced more prominent mitochondrial injury in WT cells than cGAS−/− cells (BMDM and hepatocytes), as indicated by mtDNA expression, functional mitochondria (MitoTracker), mitochondrial oxidative stress (MitoSox), and extracellular flux analysis. With alcohol activation, high anti-inflammatory genes (TGF-β and Arg-1) and low pro-inflammatory genes (low NF-κB and IL-1β) were demonstrated in cGAS−/− BMDM and hepatocytes, respectively, when compared with WT cells.In conclusion, alcohol-induced mtDNA in the cytosol of BMDM and hepatocytes leads to inflammation-induced liver damage that was less severe in cGAS−/− mice when compared to WT mice. The cGAS interference might be helpful toward attenuating alcohol-induced liver damage.