Chronic heavy drinking drives distinct transcriptional and epigenetic changes in splenic macrophages

Background: Chronic heavy alcohol drinking (CHD)leads to significant organ damage, increased susceptibility to infections, and delayed wound healing. These adverse outcomes are believed to be mediated by alterations in the function of myeloid cells; however, the mechanisms underlying these changes are poorly understood. Methods: We determined the impact of CHD on the phenotype of splenic macrophages using flow cytometry. Changes in functional responses to LPS were measured using luminex and RNA-Seq. Finally, alterations in chromatin accessibility were uncovered using ATAC-Seq. Findings: A history of CHD led to increased frequency of splenic macrophages that exhibited a heightened activation state at resting. Additionally, splenic macrophages from CHD animals generated a larger inflammatory response to LPS, both at protein and gene expression levels. Finally, CHD resulted in increased levels of H3K4me3, a histone mark of active promoters, as well as chromatin accessibility at promoters and intergenic regions that regulate inflammatory responses. Interpretation: These findings suggest that a history of CHD alters the immune fitness of tissue-resident macrophages via epigenetic mechanisms. Fund: National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH)- R24AA019431, U01 AA13641, U01 AA13510, R21AA021947, and R21AA025839.