We found that ethanol increased brain expression of HMGB1 and TLR3 as well as potentiating poly I:C induction of proinflammatory genes. In vitro studies have found ethanol increased NF-κB transcription in brain slice cultures [3,50,53], astrocytes [54] and microglial cultures [55]. Ethanol activation mimics LPS-TLR4 induction of neuroinflammation [27] and is blunted in mice lacking TLR4 receptors [27,30]. Consistent with ethanol inducing neuroinflammation, studies of postmortem human alcoholic brain have found increased expression of inflammatory genes and genes linked to increased NF-κB-DNA [56], as well as increased histochemical microglial markers and brain levels of the chemokine MCP-1 [25]. These findings indicate ethanol and poly I:C-TLR3 signaling activate NF-κB transcription consistent with ethanol priming microglia with mild activation, perhaps related to induction of HMGB1 and TLR3, that results in increased poly I:C microglial activation and induction of proinflammatory genes.
