Epigenetic targets for reversing immune defects caused by alcohol exposure

Abstract

Alcohol consumption alters factors that modify gene expression without changing the DNA code (i.e., epigenetic modulators) in many organ systems, including the immune system. Alcohol enhances the risk for developing several serious medical conditions related to immune system dysfunction, including acute respiratory distress syndrome (ARDS), liver cancer, and alcoholic liver disease (ALD). Binge and chronic drinking also render patients more susceptible to many infectious pathogens and advance the progression of HIV infection by weakening both innate and adaptive immunity. Epigenetic mechanisms play a pivotal role in these processes. For example, alcohol-induced epigenetic variations alter the developmental pathways of several types of immune cells (e.g., granulocytes, macrophages, and T-lymphocytes) and through these and other mechanisms promote exaggerated inflammatory responses. In addition, epigenetic mechanisms may underlie alcohol's ability to interfere with the barrier functions of the gut and respiratory systems, which also contribute to the heightened risk of infections. Better understanding of alcohol's effects on these epigenetic processes may help researchers identify new targets for the development of novel medications to prevent or ameliorate alcohol's detrimental effects on the immune system.

Figure 1

Chronic alcohol exposure causes immune dysfunction through effects on multiple organs. In the lungs, excessive inflammation causes tissue damage, increasing barrier permeability, and dampening many cellular immune responses, such as recognizing bacteria (through toll-like receptors [TLRs]), attacking pathogens (through phagocytosis), decreasing production of granulocytes (i.e., granulocytopenia) as well as their migration (i.e., chemotaxis), and altering important signaling and recruiting molecules (e.g., GM-CSF and chemokines). In the spleen, alcohol consumption affects immunity by decreasing T- and B-lymphocyte production. In the stomach, alcohol decreases gastric acid levels, allowing live bacteria to pass into the small intestine. Combined with decreased gastrointestinal motility, a byproduct of alcohol metabolism (i.e., acetaldehyde) increases intestinal barrier permeability by weakening cell–cell junctions, and allows bacterial toxins (i.e., lipopolysaccharide [LPS]) to pass into the bloodstream. LPS damages the liver, leading to excessive release of pro-inflammatory cytokines, leukotrienes, and ROS into the circulation. In addition, alcohol in the liver can alter macrophage (Kupffer cell) polarization and decrease phagocytosis.

Figure 2

Chronic alcohol consumption skews macrophage polarization toward an M1 (i.e., pro-inflammatory) phenotype, leading to excessive or prolonged inflammation. Two approaches using epigenetic modulators—microRNA 155 (miR-155) and histone deacetylase inhibitors—can potentionally reverse protein translation or gene transcription of M1 pro-inflammatory cytokines. Another type of enzyme—histone lysine (H3K27) demethylases—increase transcription of M2 anti-inflammatory cytokines. Factors that increase protein levels or enhance activity of H3K27 demethylases therefore may potentially be utilized to promote M2 polarization.

Figure 3

Alcohol-induced T helper cell polarization towards a Th2 phenotype suppresses immune responses. Alcohol decreases IL-12 production by antigen presenting cells, resulting in fewer naïve T-cell differentiating into Th1 cells, and blocks the release of IL-23 from macrophages, thereby preventing Th17 differentiation. Methylation of DNA or histones (H3K27) may reverse Th2 polarization.