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Neuroimmune Function and the Consequences of Alcohol Exposure.

Crews FT, Sarkar DK, Qin L, Zou J, Boyadjieva N, Vetreno RP - Alcohol Res (2015)

Bottom Line: Neuroimmune signaling and glutamate excitotoxicity are linked to alcoholic neurodegeneration.Models of alcohol abuse have identified significant frontal cortical degeneration and loss of hippocampal neurogenesis, consistent with neuroimmune activation pathology contributing to these alcohol-induced, long-lasting changes in the brain.These alcohol-induced long-lasting increases in brain neuroimmune-gene expression also may contribute to the neurobiology of alcohol use disorder.

View Article: PubMed Central - PubMed

Affiliation: Bowles Center for Alcohol Studies, University of North Carolina, Chapel Hill, North Carolina.

ABSTRACT
Induction of neuroimmune genes by binge drinking increases neuronal excitability and oxidative stress, contributing to the neurobiology of alcohol dependence and causing neurodegeneration. Ethanol exposure activates signaling pathways featuring high-mobility group box 1 and Toll-like receptor 4 (TLR4), resulting in induction of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells, which regulates expression of several cytokine genes involved in innate immunity, and its target genes. This leads to persistent neuroimmune responses to ethanol that stimulate TLRs and/or certain glutamate receptors (i.e., N-methyl-d-aspartate receptors). Alcohol also alters stress responses, causing elevation of peripheral cytokines, which further sensitize neuroimmune responses to ethanol. Neuroimmune signaling and glutamate excitotoxicity are linked to alcoholic neurodegeneration. Models of alcohol abuse have identified significant frontal cortical degeneration and loss of hippocampal neurogenesis, consistent with neuroimmune activation pathology contributing to these alcohol-induced, long-lasting changes in the brain. These alcohol-induced long-lasting increases in brain neuroimmune-gene expression also may contribute to the neurobiology of alcohol use disorder.

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Cycles of chronic alcohol consumption lead to persistently increased neuroimmune-gene expression. (Top) Repeated ethanol (EtOH) binges result in increased brain neuroimmune activation (i.e., microglial and astrocytic activation as well as upregulated neuroimmune-gene expression). (Bottom) In humans, lifetime alcohol consumption is positively correlated with neuroimmune signal immunoreactivity. Symbols indicate levels of Toll-like receptor (TLR) 2, TLR3, TLR4, and high-mobility group box 1 (HMGB1) in individual moderate drinkers and alcoholics. Results for moderate drinkers are clustered along the Y-axis because of their low lifetime alcohol consumption and similar neuroimmune expression. Alcoholic subjects show a more than 10-fold variation in lifetime alcohol consumption as well as considerable variation in expression of all four neuroimmune genes. NOTE: Correlations are as follows: TLR2: r = 0.66 (p < 0.01); TLR3: r = 0.83 (P < 0.001); TLR4: r = 0.62 (P < 0.01); HMGB1: r = 0.83 (P < 0.001).SOURCE: Crews et al. 2013.
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f4-arcr-37-2-331: Cycles of chronic alcohol consumption lead to persistently increased neuroimmune-gene expression. (Top) Repeated ethanol (EtOH) binges result in increased brain neuroimmune activation (i.e., microglial and astrocytic activation as well as upregulated neuroimmune-gene expression). (Bottom) In humans, lifetime alcohol consumption is positively correlated with neuroimmune signal immunoreactivity. Symbols indicate levels of Toll-like receptor (TLR) 2, TLR3, TLR4, and high-mobility group box 1 (HMGB1) in individual moderate drinkers and alcoholics. Results for moderate drinkers are clustered along the Y-axis because of their low lifetime alcohol consumption and similar neuroimmune expression. Alcoholic subjects show a more than 10-fold variation in lifetime alcohol consumption as well as considerable variation in expression of all four neuroimmune genes. NOTE: Correlations are as follows: TLR2: r = 0.66 (p < 0.01); TLR3: r = 0.83 (P < 0.001); TLR4: r = 0.62 (P < 0.01); HMGB1: r = 0.83 (P < 0.001).SOURCE: Crews et al. 2013.

Mentions: In humans, levels of HMGB1 and TLR expression in specific brain regions (e.g., the orbitofrontal cortex) have been shown to correlate with lifetime alcohol consumption (Crews et al. 2013) (see figure 4). Alcoholic subjects who vary greatly in the duration and amounts of active drinking bouts exhibited a large variation in lifetime alcohol consumption that correlated with increased HMGB1–TLR expression in the frontal cortex. In contrast, moderate-drinking humans consumed much less alcohol than alcoholics and exhibited much lower HMGB1–TLR expression. This interesting correlation only could occur if ethanol induction of HMGB1– TLR was persistent and cumulative with binge-drinking episodes (see figure 4). Together, these studies suggest that HMGB1–TLR4 signaling is increased by chronic binge drinking, contributing to the persistent and sustained induction of proinflammatory signaling in brain.


Neuroimmune Function and the Consequences of Alcohol Exposure.

Crews FT, Sarkar DK, Qin L, Zou J, Boyadjieva N, Vetreno RP - Alcohol Res (2015)

Cycles of chronic alcohol consumption lead to persistently increased neuroimmune-gene expression. (Top) Repeated ethanol (EtOH) binges result in increased brain neuroimmune activation (i.e., microglial and astrocytic activation as well as upregulated neuroimmune-gene expression). (Bottom) In humans, lifetime alcohol consumption is positively correlated with neuroimmune signal immunoreactivity. Symbols indicate levels of Toll-like receptor (TLR) 2, TLR3, TLR4, and high-mobility group box 1 (HMGB1) in individual moderate drinkers and alcoholics. Results for moderate drinkers are clustered along the Y-axis because of their low lifetime alcohol consumption and similar neuroimmune expression. Alcoholic subjects show a more than 10-fold variation in lifetime alcohol consumption as well as considerable variation in expression of all four neuroimmune genes. NOTE: Correlations are as follows: TLR2: r = 0.66 (p < 0.01); TLR3: r = 0.83 (P < 0.001); TLR4: r = 0.62 (P < 0.01); HMGB1: r = 0.83 (P < 0.001).SOURCE: Crews et al. 2013.
© Copyright Policy - public-domain
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4590627&req=5

f4-arcr-37-2-331: Cycles of chronic alcohol consumption lead to persistently increased neuroimmune-gene expression. (Top) Repeated ethanol (EtOH) binges result in increased brain neuroimmune activation (i.e., microglial and astrocytic activation as well as upregulated neuroimmune-gene expression). (Bottom) In humans, lifetime alcohol consumption is positively correlated with neuroimmune signal immunoreactivity. Symbols indicate levels of Toll-like receptor (TLR) 2, TLR3, TLR4, and high-mobility group box 1 (HMGB1) in individual moderate drinkers and alcoholics. Results for moderate drinkers are clustered along the Y-axis because of their low lifetime alcohol consumption and similar neuroimmune expression. Alcoholic subjects show a more than 10-fold variation in lifetime alcohol consumption as well as considerable variation in expression of all four neuroimmune genes. NOTE: Correlations are as follows: TLR2: r = 0.66 (p < 0.01); TLR3: r = 0.83 (P < 0.001); TLR4: r = 0.62 (P < 0.01); HMGB1: r = 0.83 (P < 0.001).SOURCE: Crews et al. 2013.
Mentions: In humans, levels of HMGB1 and TLR expression in specific brain regions (e.g., the orbitofrontal cortex) have been shown to correlate with lifetime alcohol consumption (Crews et al. 2013) (see figure 4). Alcoholic subjects who vary greatly in the duration and amounts of active drinking bouts exhibited a large variation in lifetime alcohol consumption that correlated with increased HMGB1–TLR expression in the frontal cortex. In contrast, moderate-drinking humans consumed much less alcohol than alcoholics and exhibited much lower HMGB1–TLR expression. This interesting correlation only could occur if ethanol induction of HMGB1– TLR was persistent and cumulative with binge-drinking episodes (see figure 4). Together, these studies suggest that HMGB1–TLR4 signaling is increased by chronic binge drinking, contributing to the persistent and sustained induction of proinflammatory signaling in brain.

Bottom Line: Neuroimmune signaling and glutamate excitotoxicity are linked to alcoholic neurodegeneration.Models of alcohol abuse have identified significant frontal cortical degeneration and loss of hippocampal neurogenesis, consistent with neuroimmune activation pathology contributing to these alcohol-induced, long-lasting changes in the brain.These alcohol-induced long-lasting increases in brain neuroimmune-gene expression also may contribute to the neurobiology of alcohol use disorder.

View Article: PubMed Central - PubMed

Affiliation: Bowles Center for Alcohol Studies, University of North Carolina, Chapel Hill, North Carolina.

ABSTRACT
Induction of neuroimmune genes by binge drinking increases neuronal excitability and oxidative stress, contributing to the neurobiology of alcohol dependence and causing neurodegeneration. Ethanol exposure activates signaling pathways featuring high-mobility group box 1 and Toll-like receptor 4 (TLR4), resulting in induction of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells, which regulates expression of several cytokine genes involved in innate immunity, and its target genes. This leads to persistent neuroimmune responses to ethanol that stimulate TLRs and/or certain glutamate receptors (i.e., N-methyl-d-aspartate receptors). Alcohol also alters stress responses, causing elevation of peripheral cytokines, which further sensitize neuroimmune responses to ethanol. Neuroimmune signaling and glutamate excitotoxicity are linked to alcoholic neurodegeneration. Models of alcohol abuse have identified significant frontal cortical degeneration and loss of hippocampal neurogenesis, consistent with neuroimmune activation pathology contributing to these alcohol-induced, long-lasting changes in the brain. These alcohol-induced long-lasting increases in brain neuroimmune-gene expression also may contribute to the neurobiology of alcohol use disorder.

Show MeSH
Related in: MedlinePlus