Crosstalk between TLRs and NLRs in the secretion of mature IL-1β during microbial infection has been reported (Kahlenberg et al., 2005; Becker and O’Neill, 2007; Mariathasan and Monack, 2007), although it is unknown whether this crosstalk occurs in brain damage and demyelination. A recent study shows that ethanol activates NLRP3 inflammasome in the brain (Lippai et al., 2013). However, the cellular and molecular mechanisms of ethanol-induced inflammasome activation in the brain and glial cells, and the interactions of TLRs and NLRs, are presently unknown. Here we present evidence for NLRP3 expression in astrocytes and that by stimulating mitochondria ROS (mROS) generation, ethanol, ATP or LPS triggers NLRP3/caspase-1 activation and the production of IL-1β and IL-18 in astrocytes. These findings further demonstrate that ethanol promotes NLRP3/caspase-1 co-localization within mitochondria to trigger pyroptosis and a small proportion of apoptosis. Elimination of the TLR4 function reduces the damaging actions of ethanol on NLRP3 inflammasome activation in astroglial cells in both primary culture and cerebral cortex in vivo, suggesting that TLR4 plays a key role in ethanol-induced NLRP3 activation, neuroinflammation and brain damage.
