MECHANISMS OF ALCOHOL-INDUCED BRAIN INNATE IMMUNE GENE INDUCTION

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CrewsFT1, VetrenoR1, MasseyV1, QinL1, ColemanL1, ZouJ1

1Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, USA

Ethanol increases expression of innate immune genes that contribute to the development of alcoholic pathology. Innate immune genes induced by binge drinking include HMGB1, multiple Toll-like receptors, RAGE, multiple cytokines, and chemokines that are increased in blood, liver, and brain. There are multiple mechanisms of ethanol induction of immune signaling proteins. In brain slice cultures, ethanol treatment releases HMGB1 from cells and increases NFkB-DNA binding and transcription of CCL2, TNFalpha, RAGE, other cytokines, and Toll-like receptors. In vivo treatment of mice with ethanol for 10 days sensitizes mice to systemic and brain proinflammatory gene induction by the TLR agonists, LPS (TLR4), Poly I:C (TLR3), and imiquimod (TLR7), in part due to ethanol induction of multiple TLR receptors in multiple tissues. Data on ethanol induction of endogenous TLR agonists and receptors will be presented. Specifically, HMGB1-TLR4, Let7-TLR7, and TNFSF15 (TL1A)-TNFSF25 (Death Receptor 3) signaling induction by ethanol will be presented. Also discussed will be studies finding each of these immune signaling agonist-receptor pairs is increased in mice treated with ethanol (C57BL6-5gm/kg/day-10days) and in post-mortem brains of alcoholics. This is consistent with ethanol consumption inducing innate immune genes in alcoholics and genetic risk being related to induction of innate immune genes. Another mechanism of increased brain innate immune signaling involves systemic TNFalpha and other cytokine activation of brain innate immune responses. Ethanol increases blood endotoxin and systemic proinflammatory cytokines, and stress combined with ethanol further increases blood endotoxin. However, responses vary depending on the amount of ethanol consumed and dynamic changes during acute exposure and withdrawal, with prominent increases once ethanol has cleared. Further, many systemic changes occur in abstinence following intoxication. Interestingly, ethanol induction in the brain shows a long-lasting persistence not found systemically. Neuroimmune signaling and glutamate excitotoxicity are linked to alcoholic neurodegeneration. Further, alcohol-induced, long-lasting increases in brain neuroimmune gene expression promote persistent and long-term increases in alcohol consumption, suggesting alcohol-induced neuroimmune activation contributes to the neurobiology of alcohol use disorders. (Funded by NIAAA)

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