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.
