Transcriptome Profiling Reveals Disruption of Innate Immunity in Chronic Heavy Ethanol Consuming Female Rhesus Macaques

Abstract

It is well established that heavy ethanol consumption interferes with the immune system and inflammatory processes, resulting in increased risk for infectious and chronic diseases. However, these processes have yet to be systematically studied in a dose and sex-dependent manner. In this study, we investigated the impact of chronic heavy ethanol consumption on gene expression using RNA-seq in peripheral blood mononuclear cells isolated from female rhesus macaques with daily consumption of 4% ethanol available 22hr/day for 12 months resulting in average ethanol consumption of 4.3 g/kg/day (considered heavy drinking). Differential gene expression analysis was performed using edgeR and gene enrichment analysis using MetaCore™. We identified 1106 differentially expressed genes, meeting the criterion of ≥ two-fold change and p-value ≤ 0.05 in expression (445 up- and 661 down-regulated). Pathway analysis of the 879 genes with characterized identifiers showed that the most enriched gene ontology processes were “response to wounding”, “blood coagulation”, “immune system process”, and “regulation of signaling”. Changes in gene expression were seen despite the lack of differences in the frequency of any major immune cell subtype between ethanol and controls, suggesting that heavy ethanol consumption modulates gene expression at the cellular level rather than altering the distribution of peripheral blood mononuclear cells. Collectively, these observations provide mechanisms to explain the higher incidence of infection, delay in wound healing, and increase in cardiovascular disease seen in subjects with Alcohol use disorder.

Gene expression profiling in the human alcoholic brain

“…Differential expression of the JAK/STAT pathway was observed in the nucleus accumbens (Mamdani et al, 2015). Alterations in JAK/STAT signaling were also found in rhesus macaques chronically exposed to ethanol (Asquith et al, 2014; Sureshchandra et al, 2016). Thus, in addition to changes in canonical TLR signaling, chronic ethanol exposure alters many other immune signaling pathways (i.e.…”

Dose-dependent effects of chronic alcohol drinking on peripheral immune responses

“…Specifically, using this model, we have shown that CMD enhances while CHD attenuates vaccine responses 42,44,47 . More recently, we reported significant transcriptional changes in PBMC from female rhesus macaque following 12 months of CHD using RNA-Seq and concluded that the circulating innate immune cells bear the largest burden of chronic heavy drinking 46 . Therefore, 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.…”

“…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. We have leveraged this model to define the impact of chronic drinking on circulating and tissue resident immune cells 41–46 . Specifically, using this model, we have shown that CMD enhances while CHD attenuates vaccine responses 42,44,47 .…”

Alcohol intake and periodontitis in adults aged ≥30 years: NHANES 2009–2012

“…in 1999 demonstrated that alcohol impairs T‐cell function and neutrophil chemotaxis, which can alter immune responses, increasing the risk of periodontitis . Ethanol modulates the function of monocytes in a dose‐ and time‐dependent manner . Monocytes also express Toll‐like receptor (TLR) 4, which is the receptor responsible for recognizing endotoxin lipopolysaccharides (LPS) on the surface of Gram‐negative bacteria .…”

“…9 Ethanol modulates the function of monocytes in a dose-and time-dependent manner. 10 Monocytes also express Toll-like receptor (TLR) 4, which is the receptor responsible for recognizing endotoxin lipopolysaccharides (LPS) on the surface of Gram-negative bacteria. 11 Upon LPS binding, monocytes become activated and mature into macrophages, which in turn migrate into tissues where they respond to infection by secreting several cytokines, resulting in the recruitment of additional leukocytes via production of chemokines and antigen presentation to T cells.…”