Chapter Eleven - Converging Actions of Alcohol on Liver and Brain Immune Signaling
Introduction
The ancient observation that alcohol consumption leads to altered behavior combined with the fact that alcoholism still poses a major public health concern according to WHO triggered broad range of investigations to reveal the underlying mechanisms of alcohol addiction and alcohol-induced neuropathology. The behavioral effects of alcohol are exerted via functional changes in the brain and excessive use of alcohol results in dementia and ataxia via neurodegeneration.
The pathogenesis of alcohol-induced changes in the brain involves neuroinflammatory and neurodegenerative changes that are partially mediated by innate immune responses (Alfonso-Loeches et al., 2010, Qin and Crews, 2012). Alcohol ingestion results in neuroinflammation (Valles, Blanco, Pascual, & Guerri, 2004) and neurodegeneration in humans and animals (Crews and Nixon, 2009, He and Crews, 2008, Qin et al., 2008). Cellular changes, inflammasome activation, proinflammatory cytokine secretion, reactive oxygen species (ROS) production, apoptosis, and changes in miRNA expression are all part of the underlying mechanism (Lippai et al., 2013, Lippai, Bala, Petrasek, et al., 2013). Inflammatory cytokines affect neurons and are associated with disease symptoms (Tracey, 2010). Toll-like receptor-4 (TLR4) signaling pathway plays an important role in the alcohol-induced production of inflammatory cytokines in different brain regions (Alfonso-Loeches et al., 2010, Lippai, Bala, Petrasek, et al., 2013). Most studies suggest that the extent of inflammation, neurodegeneration has site specificity, as the frontal, prefrontal cortical, the limbic and hippocampal as well as the cerebellar areas seem to be more affected by alcohol use than other brain regions (Alfonso-Loeches et al., 2010, Lippai et al., 2013, Qin and Crews, 2012).
Section snippets
Microglia and astrocytes
Microglia and astrocytes are the target of pathogen/danger-associated molecular patterns (P/DAMPs), and upon challenge, they become morphologically and functionally activated (Guillemin and Brew, 2004, Ridet et al., 1997, Streit et al., 1988). It has been shown that chronic alcohol administration results in increase in the number of microglia and astrocytes as well as in their functional activation in the brain, creating an environment for proinflammatory cellular and cytokine activation (
Pattern recognition receptors sense danger signals in the brain (TLRs and NLRs)
Pattern recognition receptors (PRRs), including the TLR and Nod-like receptor (NLR) families, sense evolutionary conserved molecular patterns as “danger” signals and in response, activate innate immunity and proinflammatory pathways. TLR and NLR receptors, including TLR2, TLR4, TLR6, TLR9, NLRC4, NLRP1, and NLRP3, are upregulated in the alcoholic brain (Lippai, Bala, Petrasek, et al., 2013).
TLRs are expressed on the cell surface (TLR1–TLR6) or in endosomes (TLR3, TLR7–TLR9) and upon activation
Gut–liver–brain axis
While consumed alcohol has some direct effects on the gastrointestinal tract upon contact with the mucosa, most of the biological effects of alcohol are related to its systemic distribution and delivery through the blood. It has been shown that alcohol affects the microbiome in the GI tract and alcoholics have altered and increased bacterial load in their gut (Hauge, Persson, & Danielsson, 1997). Not only the composition of the microbiome changes with alcohol use, but also the integrity of the
General consideration
Prevention and cessation of alcohol along with proper nutrition is the first line of treatment. However, this might not be enough due to the availability, the addictive effect, and the long-term effects of alcohol that also pose a major economical problem. Therefore, efforts should focus on finding a safe, effective, and economically beneficial treatment for the people suffering from the harmful consequences of alcohol use on the body, including the central nervous system.
TNFα system
Targeting the
Conclusions
Alcohol, as the most commonly used substance of abuse worldwide, is associated with multiple health effects. Excessive and prolonged alcohol use is clearly associated with harmful effects on brain both on cognitive functions and behavior. Overall, much progress was achieved in recent years in understanding mechanisms by which alcohol consumption results in neuroinflammation. Alcohol directly and indirectly via induction of danger molecules and sterile inflammation promotes sustained
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