title: Ethanol induces TLR4/TLR2 association, triggering an inflammatory response in microglial cells.
abstract: Alcohol consumption can induce brain damage, demyelination, and neuronal death, although the mechanisms are poorly understood. Toll-like receptors are sensors of the innate immune system and their activation induces inflammatory processes. We have reported that ethanol activates and recruits Toll-like receptor (TLR)4 receptors within the lipid rafts of glial cells, triggering the production of inflammatory mediators and causing neuroinflammation. Since TLR2 can also participate in the glial response and in the neuroinflammation, we investigate the effects of ethanol on TLR4/TLR2 responses. Here, we demonstrate that ethanol up-regulates TLR4 and TLR2 expression in microglial cells, inducing the production of inflammatory mediators which triggers reactive oxygen species generation and neuronal apoptosis. Ethanol also promotes TLR4/TLR2 recruitment into lipid rafts-caveolae, mimicking their activation by their ligands, lipopolysaccharide, and lipoteichoic acid (LTA). Immunoprecipitation and confocal microscopy studies reveal that ethanol induces a physical association between TLR2 and TLR4 receptors, suggesting the formation of heterodimers. Using microglia from either TLR2 or TLR4 knockout mice, we show that TLR2 potentiates the effects of ethanol on the TLR4 response reflected by the activation of MAPKs and inducible NO synthase. In summary, we provide evidence for a mechanism by which ethanol triggers TLR4/TLR2 association contributing to the neuroinflammation and neurodegeneration associated with alcohol abuse.
authors.affiliation: Department of Cellular Pathology, Príncipe Felipe Research Centre, Eduardo Primo Yúfera, Valencia, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Fernandez-Lizarbe
authors.forename: Jorge
authors.initials: J
authors.lastname: Montesinos
authors.forename: Consuelo
authors.initials: C
authors.lastname: Guerri
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D021941:Caveolae / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D002540:Cerebral Cortex; D016207:Cytokines / Q000378:metabolism; D004735:Energy Transfer; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D007249:Inflammation; D008070:Lipopolysaccharides / Q000494:pharmacology; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000378:metabolism*
chemical_list: D002492:Central Nervous System Depressants; D016207:Cytokines; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D000431:Ethanol; D019001:Nitric Oxide Synthase; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: TLRs; apoptosis; ethanol; immunopathology; inflammation; lipid rafts