Taken together, the observations indicate that chronic ethanol sensitizes both systemic and brain responses to neuroimmune-gene activation through induction of HMGB1 and TLR proteins. Ethanol-induced leaky gut occurs after high binge-drinking doses, with gut ethanol exposure often being equivalent to the beverage content (i.e., 80 proof is 40 percent ethanol). As a result, bacterial products enter the circulation to the liver and activate liver monocytes (i.e., Kupffer cells), which then produce cytokines, including TNF-α. The TNF-α can be transported to the brain, activating brain neuroimmune signaling that persists for long periods (Qin et al. 2007). Thus, at least two mechanisms of ethanol activation of neuroimmune signaling exist—a direct activation within the brain and the spread of a systemic innate immune activation to the brain (figure 6).
