Ethanol induces neuroimmune genes through multiple mechanisms. One mechanism involves alcohol-induced release of HMGB1,2 which increases NF-κB–mediated transcription of proinflammatory cytokines (Crews et al. 2013; Zou and Crews 2014). Several transmitters and neuroimmune-signaling receptors as well as neuronal excitability increase the release of HMGB1 (Maroso et al. 2010). This protein is a TLR4 agonist that acts through multiple signaling mechanisms in the brain, thereby influencing astrocytes and microglia, as well as neurogenesis, neurite growth, and excitability in adjacent neurons. HMGB1 released by neuronal activity stimulates TLR4 receptors, resulting in IL-1β release and increased phosphorylation of a subunit of the NMDA receptor (i.e., the NR2B subunit), which in turn increases susceptibility to seizures (Maroso et al. 2010; Vezzani et al. 2011). Actively released HMGB1 is acetylated, and ethanol increases HMGB1 acetylation in brain slice cultures. The acetyl-HMGB1 initially is found primarily in the cell’s cytosol, likely in vesicles, before its concentration in the surrounding fluid increases progressively, consistent with neuronal release (Zou and Crews 2014). The importance of ethanol-induced release of HMGB1 and resulting TLR4 activation to ethanol-induced neurodegeneration and behavioral
