Abstract
It is well established that chronic heavy alcohol drinking (CHD) results in significant organ damage, increased susceptibility to infections, and poor outcomes following injury. In contrast, chronic moderate drinking (CMD) has been associated with improved cardiovascular health and immunity. These differential outcomes have been linked to alterations in both innate and adaptive branches of the immune system; however, the mechanisms remain poorly understood. To address this question, we determined the impact of chronic drinking on the transcriptional and functional responses of peripheral blood mononuclear cells (PBMC) collected from male rhesus macaques classified as CMD or CHD after 12 months of voluntary ethanol self-administration. Our analysis suggests that chronic alcohol drinking, regardless of dose alters resting transcriptomes of PBMC, with the largest impact seen in innate immune cells. These transcriptional changes are partially explained by alterations in microRNA profiles. Additionally, chronic alcohol drinking is associated with a dose dependent heightened inflammatory profiled at resting and following LPS stimulation. Moreover, we observed a dose-dependent shift in the kinetics of transcriptional responses to LPS. These findings may explain the dichotomy in clinical and immunological outcomes observed with moderate versus heavy alcohol drinking.
Highlights
Observational studies in humans have reported strong associations between chronic heavy drinking (CHD) and significant organ damage as indicated by increased incidence of acute respiratory stress syndrome (ARDS)[1], alcoholic liver disease (ALD)[2], certain cancers[3,4,5], cardiovascular diseases[6,7], and sepsis[8]
To assess the overall impact of chronic drinking on peripheral immune cells, we performed RNA-Seq on peripheral blood mononuclear cells (PBMC) isolated from three control animals and eight animals categorized as “chronic moderate drinkers” (CMD) (n = 4) or “chronic heavy drinkers” (CHD) (n = 4) at the end of 12 months of ethanol self-administration (Supplementary Fig. 1a–c)
Principal Component Analysis (PCA) of PBMC transcriptomes demonstrate a substantial effect of chronic drinking, where transcriptional profiles of samples obtained from chronic moderate drinking (CMD) and chronic heavy alcohol drinking (CHD) animals segregate away from those of control animals (Fig. 1a)
Summary
Observational studies in humans have reported strong associations between chronic heavy drinking (CHD) and significant organ damage as indicated by increased incidence of acute respiratory stress syndrome (ARDS)[1], alcoholic liver disease (ALD)[2], certain cancers[3,4,5], cardiovascular diseases[6,7], and sepsis[8]. While short-term exposure increased production of regulatory cytokines (e.g. IL-10) and decreased production of pro-inflammatory factors (TNFα and IL-6)[28,29,30], long-term exposure heightened TNFα secretion following stimulation with toll-like receptor (TLR) 4 and 8 ligands[29,31,32] These in vitro studies do not take into account the effects of ethanol’s metabolites and the pleiotropic impact of ethanol consumption on other immune cells, which can be modeled only using in vivo exposure. During the open access phase to the protocol, the monkeys self-select their drinking status (CHD or CMD) This model presents a unique opportunity to study the impact of chronic voluntary moderate/heavy drinking on immunity in a highly translational outbred animal model without any overt tissue damage. In this study, we investigated the impact of both CHD and CMD on PBMC transcriptional profile and immune mediator production at resting and after stimulation with lipopolysaccharide (LPS) using samples obtained from three cohorts of male rhesus macaques that followed a standard protocol of daily open-access to 4% ethanol in water solution for over 12 months
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
