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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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Simplified schematic depicting how neuroimmune signaling leads to neuronal hyperexcitability and the neurobiology of addiction. Alcohol and stress activate neurons and glia in the central nervous system, resulting in the release of various neuroimmune signals (e.g., high-mobility group box 1 [HMGB1] and interleukin-1beta [IL-1β]) that activate neuroimmune receptors (e.g., Toll-like receptors [TLRs]). Neuroimmune receptor stimulation leads to phosphorylation, and thus activation, of glutamatergic N-methyl-d-aspartate (NMDA) receptors that are transported to the cell surface (Iori et al. 2013; Maroso et al. 2010). The increased number of NMDA receptors increases Ca2+ flux, triggering further induction of neuroimmune genes, and also promotes glutamate hyperexcitability and excitotoxicity.
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f5-arcr-37-2-331: Simplified schematic depicting how neuroimmune signaling leads to neuronal hyperexcitability and the neurobiology of addiction. Alcohol and stress activate neurons and glia in the central nervous system, resulting in the release of various neuroimmune signals (e.g., high-mobility group box 1 [HMGB1] and interleukin-1beta [IL-1β]) that activate neuroimmune receptors (e.g., Toll-like receptors [TLRs]). Neuroimmune receptor stimulation leads to phosphorylation, and thus activation, of glutamatergic N-methyl-d-aspartate (NMDA) receptors that are transported to the cell surface (Iori et al. 2013; Maroso et al. 2010). The increased number of NMDA receptors increases Ca2+ flux, triggering further induction of neuroimmune genes, and also promotes glutamate hyperexcitability and excitotoxicity.

Mentions: Another mechanism contributing to alcoholic neurodegeneration and associated with HMGB1–TLR4 signaling is the excessive stimulation of receptors that results in neuron damage and cell death (i.e., excitotoxicity). Chronic ethanol treatment of neurons leads to increased sensitivity to excitotoxicity (Chandler et al. 1994). This effect primarily involves the neuro-transmitter glutamate and its receptors. However, the relationship between ethanol and glutamate receptors is complex. Thus, although ethanol enhances overall glutamate excitotoxicity, in neuronal primary cultures it blocks excitotoxicity associated with a specific type of glutamate receptor (i.e., the NMDA receptor). This is consistent with many studies finding that ethanol inhibits NMDA receptors (Chandler et al. 1998). Yet at the same time, HMGB1–TLR4 signaling (Balosso et al. 2014) and IL-1β receptor signaling (Viviani et al. 2003)—both of which, as described above, are induced by chronic ethanol—increase NMDA receptor-mediated calcium flux, neuronal excitability, and excitotoxicity through activation of kinase signaling cascades, including activation of Src kinase and tyrosine-kinase (see figure 5). Furthermore, Suvarna and colleagues (2005) found that ethanol increases NMDA excitability in the hippocampus through kinase activation that alters receptor trafficking, leading to increased numbers of NMDA receptors containing the NR2B subunit at the synapse.


Neuroimmune Function and the Consequences of Alcohol Exposure.

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

Simplified schematic depicting how neuroimmune signaling leads to neuronal hyperexcitability and the neurobiology of addiction. Alcohol and stress activate neurons and glia in the central nervous system, resulting in the release of various neuroimmune signals (e.g., high-mobility group box 1 [HMGB1] and interleukin-1beta [IL-1β]) that activate neuroimmune receptors (e.g., Toll-like receptors [TLRs]). Neuroimmune receptor stimulation leads to phosphorylation, and thus activation, of glutamatergic N-methyl-d-aspartate (NMDA) receptors that are transported to the cell surface (Iori et al. 2013; Maroso et al. 2010). The increased number of NMDA receptors increases Ca2+ flux, triggering further induction of neuroimmune genes, and also promotes glutamate hyperexcitability and excitotoxicity.
© Copyright Policy - public-domain
Related In: Results  -  Collection

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

f5-arcr-37-2-331: Simplified schematic depicting how neuroimmune signaling leads to neuronal hyperexcitability and the neurobiology of addiction. Alcohol and stress activate neurons and glia in the central nervous system, resulting in the release of various neuroimmune signals (e.g., high-mobility group box 1 [HMGB1] and interleukin-1beta [IL-1β]) that activate neuroimmune receptors (e.g., Toll-like receptors [TLRs]). Neuroimmune receptor stimulation leads to phosphorylation, and thus activation, of glutamatergic N-methyl-d-aspartate (NMDA) receptors that are transported to the cell surface (Iori et al. 2013; Maroso et al. 2010). The increased number of NMDA receptors increases Ca2+ flux, triggering further induction of neuroimmune genes, and also promotes glutamate hyperexcitability and excitotoxicity.
Mentions: Another mechanism contributing to alcoholic neurodegeneration and associated with HMGB1–TLR4 signaling is the excessive stimulation of receptors that results in neuron damage and cell death (i.e., excitotoxicity). Chronic ethanol treatment of neurons leads to increased sensitivity to excitotoxicity (Chandler et al. 1994). This effect primarily involves the neuro-transmitter glutamate and its receptors. However, the relationship between ethanol and glutamate receptors is complex. Thus, although ethanol enhances overall glutamate excitotoxicity, in neuronal primary cultures it blocks excitotoxicity associated with a specific type of glutamate receptor (i.e., the NMDA receptor). This is consistent with many studies finding that ethanol inhibits NMDA receptors (Chandler et al. 1998). Yet at the same time, HMGB1–TLR4 signaling (Balosso et al. 2014) and IL-1β receptor signaling (Viviani et al. 2003)—both of which, as described above, are induced by chronic ethanol—increase NMDA receptor-mediated calcium flux, neuronal excitability, and excitotoxicity through activation of kinase signaling cascades, including activation of Src kinase and tyrosine-kinase (see figure 5). Furthermore, Suvarna and colleagues (2005) found that ethanol increases NMDA excitability in the hippocampus through kinase activation that alters receptor trafficking, leading to increased numbers of NMDA receptors containing the NR2B subunit at the synapse.

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