Uncovering the functional and mechanistic dysregulation of monocytes after abstinence and post-abstinence drinking

Over 85% of individuals 18-years and older within the United States (US) consume alcohol. More importantly, a staggering 25.8% and 6.3% are classified by the National Institute on Alcohol Abuse and Alcoholism criteria as binge or heavy drinkers, respectively, making alcohol the 3rd leading cause of preventable death. Chronic heavy

drinking (CHD) increases the incidence of heart disease, stroke, cancer, and alcoholic liver disease. CHD is also associated with heightened susceptibility to bacterial/viral pathogens and tissue repair mechanisms, suggesting alcohol consumption negatively impacts the immune system. Indeed, studies from our group and others have

reported functional, transcriptional, and epigenetic modifications in peripheral monocytes and tissue-resident macrophages with CHD, skewing them toward a hyper-inflammatory phenotype while impairing pathogen defense mechanisms. Despite the significant contribution of aberrant monocyte/macrophage responses to CHD-

induced organ injury, no studies to date have investigated the effects of abstinence and post-abstinence drinking on these critical cells. Organs and organ systems after alcohol consumption (brain, liver, lung) are challenging to interrogate throughout repeated bouts of abstinence and post-abstinence drinking. Since circulating

monocytes are precursors of some tissue-resident macrophages, investigating the effects of abstinence and relapse on circulating monocytes will provide greater insight into how CHD dysregulates organs and organ systems. In this application, we will leverage a rhesus macaque model of voluntary ethanol self-administration

to test the hypothesis that CHD induces persistent functional, transcriptional, and epigenetic changes in peripheral monocytes that are not reversed by short periods of abstinence and are exacerbated by repeated bouts of abstinence and post-abstinence drinking. This hypothesis will be tested using a multi-

pronged approach using multiplex ELISA, flow cytometry, single cell omics, and metabolic assays after a 28-day abstinence and post-abstinence drinking episodes. These experiments will provide deeper insight into the persistence of CHD-induced immune modifications in complex organs and organ systems. This understanding

could identify novel druggable targets that decrease alcohol cravings or organ damage/opportunistic infections that occur after CHD.