The role of TLR4 in ethanol-induced neuroinflammation and brain damage has been clearly demonstrated. Our previous studies have shown that by interacting with membrane microdomains “lipid rafts” in glial cells, ethanol can induce TLR4 dimerization and signaling to trigger the release of cytokines and inflammatory mediators (Blanco et al., 2005, 2008; Fernandez-Lizarbe et al., 2009). By using small interfering RNA (siRNA) or cells from TLR4-deficient mice (TLR4-KO), knockdown TLR4, abolish MAPK and NFk-B signaling pathways and the release of inflammatory mediators in glial cells (Fernandez-Lizarbe et al., 2009; Alfonso-Loeches et al., 2010). The in vivo relevance of these findings is evidenced by the demonstration that while chronic ethanol intake causes neuroinflammation, gliosis, demyelination and cell death (apoptosis and necrosis) in the cerebral cortex, TLR4-KO mice are protected against ethanol-induced brain inflammatory mediators, cell death and brain injury (Alfonso-Loeches et al., 2010, 2012). The present findings further support the role of TLR4 in ethanol-induced NLRP3 inflammasome activation and IL-1β and IL-18 production in glial cells, events that contribute to ethanol-induced neuroinflammation. To support our results, a recent study has demonstrated that
