Microglial-specific transcriptome changes following chronic alcohol consumption

Abstract

Microglia are fundamentally important immune cells within the central nervous system (CNS) that respond to environmental challenges to maintain normal physiological processes. Alterations in steady-state cellular function and over-activation of microglia can facilitate the initiation and progression of neuropathological conditions such as Alzheimer’s disease, Multiple Sclerosis, and Major Depressive Disorder. Alcohol consumption disrupts signaling pathways including both innate and adaptive immune responses that are necessary for CNS homeostasis. Coordinate expression of these genes is not ascertained from an admixture of CNS cell-types, underscoring the importance of examining isolated cellular populations to reveal systematic gene expression changes arising from mature microglia. Unbiased RNA-Seq profiling was used to identify gene expression changes in isolated prefrontal cortical microglia in response to recurring bouts of voluntary alcohol drinking behavior. The voluntary ethanol paradigm utilizes long-term consumption ethanol that results in escalated alcohol intake and altered cortical plasticity that is seen in humans. Gene coexpression analysis identified a coordinately regulated group of genes, unique to microglia, that collectively are associated with alcohol consumption. Genes within this group are involved in toll-like receptor signaling and transforming growth factor beta signaling. Network connectivity of this group identified Siglech as a putative hub gene and highlighted the potential importance of proteases in the microglial response to chronic ethanol. In conclusion, we identified a distinctive microglial gene expression signature for neuroimmune responses related to alcohol consumption that provides valuable insight into microglia-specific changes underlying the development of substance abuse, and possibly other CNS disorders.

Inhibition of the Inflammasome Signaling Cascade Reduces Alcohol Consumption in Female But Not Male Mice

“…Longer‐term models of 2‐bottle choice offer intermittent alcohol with alcohol‐free days in between. Studies after thirty days of alcohol (60 days total) have revealed significant changes in microglia and astrocyte gene expression with significantly up‐regulated microglial immune signaling (Erickson et al, ; McCarthy et al, ) and may be an interesting alternative model to investigate with inflammasome inhibition in order to achieve more significant inflammation. Indeed, these models may offer avenues to study expression of inflammasome components and other proinflammatory biochemical signals in the setting of alcohol and inhibitor treatments, measurements we were unable to assess in this current self‐administration paradigm.…”

Alcohol Modulates the Biogenesis and Composition of Microglia-Derived Exosomes

“…Exosomes have been shown to play a vital role in microglia function [11,12,13]. Microglia are the primary immune cells within the central nervous system (CNS) that regulate inflammatory processes during infection or cellular damage [9,12,14]. Upon activation, microglia undergo complex morphological and functional transitions, which includes increased phagocytosis, motility, and cytokine secretion [9].…”

“…Microglia secrete exosomes due to stress stimulated by alcohol consumption. Alcohol consumption disrupts signaling pathways (i.e., innate and adaptive immune responses) that are necessary for CNS homeostasis [14]. As a small molecule, alcohol can easily cross membrane barriers and reach different parts of the body very quickly, which can lead to total body alteration.…”

Time course of microglia activation and brain and blood cytokine/chemokine levels following chronic ethanol exposure and protracted withdrawal in rats

“…Post-mortem brains from alcoholics contain microglia at all four stages but are enriched in hyper-ramified microglia suggesting that ethanol sensitizes these cells (see (Crews & Vetreno, 2016). Further studies have demonstrated that microglial responses vary according to the duration, dose and pattern of alcohol exposure (Henriques et al, 2018;McCarthy et al, 2018;Yang et al, 2014). Very large doses of alcohol (Crews, 2008;Peng et al, 2017;Zahr et al, 2010), repeated cycles of ethanol exposure (Marshall et al, 2016;Zhao et al, 2013) or prior ethanol exposure are known to produce elevated levels of serum cytokines as well as microglia activation and long lasting increases in neuroimmune gene induction suggesting microglia priming (Crews & Vetreno, 2016;Perry & Holmes, 2014;Zou & Crews, 2010).…”