Epigenetic basis for monocyte dysfunction in acute-on-chronic liver failure and alcoholic hepatitis [ATAC-seq]

BACKGROUND/ AIMS: Severe forms of alcoholic liver disease are associated with increased susceptibility to infections largely due to immune dysfunction. In this study, we analyze the phenotypic, molecular and functional profiles of the mononuclear phagocyte system of patients with cirrhosis, severe alcoholic hepatitis (sAH) or acute-on-chronic liver failure (ACLF). RESULTS: sAH and ACLF patients display a severe impairment of the TH1-promoting IL-12p70/IFNgamma/CXCL10 axis. Furthermore, the CD14+ monocytes and classical dendritic cells of these patients are unable to mount an appropriate pro-inflammatory response after stimulation with PAMPs associated with gram-negative bacteria or fungal pathogens. These cells also have reduced polyfunctionality, which is associated with a higher risk of subsequent infection. Finally, we show that CD14+ monocytes of sAH and ACLF patients display a similar transcriptional profile characterized by immunosuppressive features. This was accompanied with changes in chromatin accessibility in enhancer regions of key immune and metabolic genes. CONCLUSIONS: Altered transcriptional program and functional properties of monocytes from sAH and ACLF patients has strong epigenetic determinants. Overall design: We recruited 39 patients with alcoholic cirrhosis (including 11 patients with sAH and 12 with ACLF), 12 healthy controls and 11 patients with chronic alcohol consumption. We performed whole blood phenotypic analysis of surface markers and stimulation with various pathogen-associated molecular patterns (PAMPs). We also performed RNAseq and ATACseq on CD14+ monocytes from 6 HC, 4 sHA and 4 ACLF patients.