While it is unclear if the presence of acute ethanol exposure antagonizes TLR4 on all cell types, other TLRs are not acutely blocked by ethanol (Crews et al. 2006a). Upregulation of TLRs by chronic alcohol treatment can lead to sensitization. In mice, binge treatment with ethanol for 10 days (5 g/kg/day), followed by LPS 24 hours later when alcohol had cleared, resulted in a marked increase in proinflammatory gene induction (Qin and Crews 2012b). Ethanol treatment increased the responses to LPS-induced proinflammatory cytokines in liver, blood, and brain. The responses were transient in blood and liver but were long lasting in brain. Similarly, chronic 10-day alcohol treatment sensitized mice to the proinflammatory response to Poly:IC, a compound that activates TLR3 (Qin and Crews 2012a). Thus, the effects of ethanol on brain neuroimmune signaling are in part related to increases in TLRs (see figure 1) that increase neuroimmune signaling and cytokines, such as IL-1β, during chronic ethanol treatment, although the presence of alcohol can blunt TLR4 responses during intoxication.
