Abstract
Chronic heavy drinking (CHD) of alcohol is a known risk factor for increased susceptibility to bacterial and viral infection as well as impaired wound healing. Evidence suggests that these defects are mediated by a dysregulated inflammatory response originating from myeloid cells, notably monocytes and macrophages, but the mechanisms remain poorly understood. Our ability to study CHD is impacted by the complexities of human drinking patterns and behavior as well as comorbidities and confounding risk factors for patients with alcohol use disorders. To overcome these challenges, we utilized a translational rhesus macaque model of voluntary ethanol self-administration that closely recapitulates human drinking patterns and chronicity. In this study, we examined the effects of CHD on blood monocytes in control and CHD female macaques after 12 months of daily ethanol consumption. While monocytes from CHD female macaques generated a hyper-inflammatory response to ex vivo LPS stimulation, their response to E. coli was dampened. In depth scRNA-Seq analysis of purified monocytes revealed significant shifts in classical monocyte subsets with accumulation of cells expressing markers of hypoxia (HIF1A) and inflammation (NFkB signaling pathway) in CHD macaques. The increased presence of monocyte subsets skewed towards inflammatory phenotypes was complemented by epigenetic analysis, which revealed higher accessibility of promoter regions that regulate genes involved in cytokine signaling pathways. Collectively, data presented in this manuscript demonstrate that CHD shifts classical monocyte subset composition and primes the monocytes towards a more hyper-inflammatory response to LPS, but compromised pathogen response.
Highlights
Alcohol consumption is widespread in the United States with 85% of individuals ages 18 and older engaging in this behavior
Recent bulk RNA seq analysis of resting peripheral blood mononuclear cells (PBMC) obtained from female rhesus macaques after 12 months of chronic heavy drinking (CHD) indicated that most of the differential gene expression originated from innate immune cells [monocytes and dendritic cells (DCs)] [18]
To assess if CHD led to changes in inflammatory responses by circulating innate immune cells in female macaques, PBMC obtained from CHD (n=6) and control (n=3) females were stimulated ex vivo with LPS for 16 hours followed by measurement of immune mediator production by Luminex assay and transcriptional changes by bulk RNA Seq (Supplementary Figure 1A)
Summary
Alcohol consumption is widespread in the United States with 85% of individuals ages 18 and older engaging in this behavior. While most of these individuals are considered moderate drinkers, 7% are classified as heavy alcohol users (National Survey on Drug Use and Health, 2015). CHD compromises tissue repair, resulting in reduced post-operative healing and poor trauma recovery outcomes [14, 15]. These observations strongly suggest that CHD dysregulates immunity and host defense
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