title: Ethanol-Induced TLR4/NLRP3 Neuroinflammatory Response in Microglial Cells Promotes Leukocyte Infiltration Across the BBB.
abstract: We reported that the ethanol-induced innate immune response by activating TLR4 signaling triggers gliosis and neuroinflammation. Ethanol also activates other immune receptors, such as NOD-like-receptors, and specifically NLRP3-inflammasome in astroglial cells, to stimulate caspase-1 cleavage and IL-1β and IL-18 cytokines production. Yet, whether microglia NLRs are also sensitive to the ethanol effects that contribute to neuroinflammation is uncertain. Using cerebral cortexes of the chronic alcohol-fed WT and TLR4(-/-) mice, we demonstrated that chronic ethanol treatment enhanced TLR4 mediated-NLRP3/Caspase-1 complex activation, and up-regulated pro-inflammatory cytokines and chemokines levels. Ethanol-induced NLRP3-inflammasome activation and mitochondria-ROS generation were also observed in cultured microglial cells. The up-regulation of CD45(high)/CD11b(+) cell populations and matrix metalloproteinase-9 levels was also noted in the cortexes of the ethanol-treated WT mice. Notably, elimination of the TLR4 function abolished most ethanol-induced neuroinflammatory effects. Thus, our results demonstrate that ethanol triggers TLR4-mediated NLRP3-inflammasome activation in glial cells, and suggest that microglia stimulation may compromise the permeability of blood-brain barrier events to contribute to ethanol-induced neuroinflammation and brain damage.
authors.affiliation: Molecular and Cellular Pathology of Alcohol, Prince Felipe Research Center, Eduardo Primo Yúfera 3, 46012, Valencia, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Alfonso-Loeches
authors.affiliation: Molecular and Cellular Pathology of Alcohol, Prince Felipe Research Center, Eduardo Primo Yúfera 3, 46012, Valencia, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Ureña-Peralta
authors.affiliation: Molecular and Cellular Pathology of Alcohol, Prince Felipe Research Center, Eduardo Primo Yúfera 3, 46012, Valencia, Spain.
authors.forename: M José
authors.initials: MJ
authors.lastname: Morillo-Bargues
authors.affiliation: Department of Regenerative Medicine/Neurology and Neurosurgery, Neuroscience Institute, Clinic San Carlos Hospital, IdISSC, Profesor Martín Lagos, S/N, 28040, Madrid, Spain.
authors.forename: Ulises
authors.initials: U
authors.lastname: Gómez-Pinedo
authors.affiliation: Molecular and Cellular Pathology of Alcohol, Prince Felipe Research Center, Eduardo Primo Yúfera 3, 46012, Valencia, Spain. guerri@cipf.es.
authors.forename: Consuelo
authors.initials: C
authors.lastname: Guerri
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D002352:Carrier Proteins / Q000502:physiology*; D002490:Central Nervous System / Q000166:cytology / Q000187:drug effects; D000431:Ethanol / Q000633:toxicity*; D005260:Female; D007962:Leukocytes / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000166:cytology / Q000187:drug effects*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D051197:Toll-Like Receptor 4 / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D000431:Ethanol
keywords: Alcohol; BBB; Leukocyte infiltration; Matrix metalloproteinase; Microglia; TLR4