Critical role of TLR4 response in the activation of microglia induced by ethanol.
Microglial cells are the primary immune effector cells in the brain and play a pivotal role in the neuroinflammatory processes associated with a variety of neurological and pathological disorders. Alcohol consumption induces brain damage, although the neuropathological processes are poorly understood. We previously suggested that ethanol promotes inflammatory processes in the brain, up-regulating inflammatory mediators and signaling pathways associated with IL-1RI/TLR4 receptors. In the present study we investigate whether ethanol induces microglia activation by stimulating TLR4 response and whether this response causes neuronal death and contributes to ethanol-induced neuroinflammatory damage. We demonstrate that ethanol activates microglía and stimulates NF-kappaB, MAPKs, and MyD88-independent (IFN regulatory factor-3, IFN-beta) pathways to trigger the production of inflammatory mediators, causing neuronal death. The inflammatory response induced by ethanol is completely abrogated in microglia of TLR4-deficient mice (TLR4(-/-)), thus supporting the role of these receptors in microglia activation and neuronal death. In accord with the in vitro findings, acute ethanol administration induces microglia activation (CD11b(+) cells) in cerebral cortex of TLR4(+/+) mice, but not in TLR4(-/-) mice. Taken together, our results not only provide the first evidence of the critical role of the TLR4 response in the ethanol-induced microglia activation, but also new insight into the basic mechanisms participating in ethanol-induced neuroinflammatory damage.
Fernandez-Lizarbe
Sara
S
Department of Cellular Pathology, Centro de Investigación Príncipe Felipe, Valencia 46012, Spain.
Pascual
Maria
M
Guerri
Consuelo
C
D000818:Animals; D000831:Animals, Newborn; D016923:Cell Death / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D000431:Ethanol / Q000008:administration & dosage*; D005260:Female; D018836:Inflammation Mediators / Q000008:administration & dosage* / Q000378:metabolism / Q000502:physiology*; D007274:Injections, Intraperitoneal; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D018836:Inflammation Mediators; C493487:Tlr4 protein, mouse; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D000431:Ethanol