Chronic Heavy Drinking Drives Distinct Transcriptional and Epigenetic Changes in Splenic Macrophages

Abstract

Chronic heavy alcohol drinking (CHD) leads to significant organ damage, increased susceptibility to infections and poor outcomes following injury. These adverse outcomes are linked to alterations in myeloid cells, potentially regulated at the epigenetic level. We determined the impact of CHD on the transcriptional and functional responses of splenic macrophages collected from rhesus macaques after at least 12 months of continuous ethanol self-administration. CHD led to increased frequency of splenic macrophages that exhibited a higher basal activation state and generated heightened inflammatory responses to LPS, both at protein and gene expression levels. Furthermore, CHD resulted in significant epigenetic reprogramming, increasing global active promoter histone levels (H3K4me3) and chromatin accessibility at promoters and intergenic regions regulating inflammatory responses. These findings suggest that long-term alcohol consumption alters the immune fitness of tissue resident myeloid cells via epigenetic mechanisms. Funding Statement: This work has been funded by NIH 8P51 ODO11092-533, NIH/NIAAA R24AA019431, U01 AA13641, U01 AA13510 and NIH/NIAAA R21AA021947 and R21AA025839. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: This study was performed in strict accordance with the recommendations made in the Guide for Care and Use of Laboratory Animals of the National Institutes of Health, the Office of Animal Welfare and the United States Department of Agriculture. The ONPRC Institutional Animal Care and Use Committee approved all animal work.