Impact of Chronic Alcohol Consumption on the Functional and Epigenetic Landscapes of Monocytes and their Progenitors

Alcohol misuse is prevalent in the United States, with 10.5% of people ages 12 or older suffering from alcohol use disorder (AUD) in 2021. Chronic alcohol consumption (CAC) is associated with adverse health outcomes including increased incidence of infectious diseases, alcoholic liver disease, cancer, cardiovascular disease as well as impaired wound and bone healing. These findings suggest alcohol misuse negatively impacts the immune system, and particularly monocytes and macrophages which play critical roles in tissue homeostasis and antimicrobial defense. During the previous funding cycle, we showed that CAC is associated with elevated secretion of proinflammatory cytokines and impaired host defense in circulating monocytes and tissue resident macrophages. Importantly, this phenotype was also observed in bone marrow myeloid progenitor cells, and we showed that CAC leads to vascular remodeling of the bone marrow niche characterized by a reduction of primitive hematopoietic stem and progenitor cells (HSPC) as well as a shift in localization of HSPC from an adipose to a perivascular niche. Moreover, we reported shifts in cell states, chromatin accessibility, and histone marks with CAC. These findings indicate CAC shifts transcriptional, functional, and epigenetic profiles of monocytes to a hyper-inflammatory state but the mechanisms by which CAC alters specific subsets of monocytes and their bone marrow progenitors remain poorly understood. To address this knowledge gap, we will continue to leverage a well-established macaque model of voluntary ethanol self-administration that recapitulates the hallmarks of alcohol drinking in humans to test the central hypothesis that dysregulation of the gut microbiota coupled with the loss of barrier integrity due to chronic alcohol consumption leads to translocation of microbial products that reprogram monocytes and HSPC towards a hyperinflammatory response with reduced functional capacity. The novelty of this renewal application lies in the systems biology approach that integrates metabolomic and functional data with transcriptional and epigenetic readouts at the single cell level in monocytes and their bone marrow progenitors. Completion of the proposed experiments will uncover the molecular mechanisms underlying the detrimental effect of CAC on monocytes and their progenitors, thus enabling a better understanding of the etiology of chronic inflammation caused by CAC.