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.

Grant Number: 5F31AA031600-02
NIH Institute/Center: NIH
Principal Investigator: Madison Blanton