title: Alcohol-induced IL-1β in the brain is mediated by NLRP3/ASC inflammasome activation that amplifies neuroinflammation.
abstract: Alcohol-induced neuroinflammation is mediated by proinflammatory cytokines, including IL-1β. IL-1β production requires caspase-1 activation by inflammasomes-multiprotein complexes that are assembled in response to danger signals. We hypothesized that alcohol-induced inflammasome activation contributes to increased IL-1β in the brain. WT and TLR4-, NLRP3-, and ASC-deficient (KO) mice received an ethanol-containing or isocaloric control diet for 5 weeks, and some received the rIL-1ra, anakinra, or saline treatment. Inflammasome activation, proinflammatory cytokines, endotoxin, and HMGB1 were measured in the cerebellum. Expression of inflammasome components (NLRP1, NLRP3, ASC) and proinflammatory cytokines (TNF-α, MCP-1) was increased in brains of alcohol-fed compared with control mice. Increased caspase-1 activity and IL-1β protein in ethanol-fed mice indicated inflammasome activation. TLR4 deficiency protected from TNF-α, MCP-1, and attenuated alcohol-induced IL-1β increases. The TLR4 ligand, LPS, was not increased in the cerebellum. However, we found up-regulation of acetylated and phosphorylated HMGB1 and increased expression of the HMGB1 receptors (TLR2, TLR4, TLR9, RAGE) in alcohol-fed mice. NLRP3- or ASC-deficient mice were protected from caspase-1 activation and alcohol-induced IL-1β increase in the brain. Furthermore, in vivo treatment with rIL-1ra prevented alcohol-induced inflammasome activation and IL-1β, TNF-α, and acetylated HMGB1 increases in the cerebellum. Conversely, intracranial IL-1β administration induced TNF-α and MCP-1 in the cerebellum. In conclusion, alcohol up-regulates and activates the NLRP3/ASC inflammasome, leading to caspase-1 activation and IL-1β increase in the cerebellum. IL-1β amplifies neuroinflammation, and disruption of IL-1/IL-1R signaling prevents alcohol-induced inflammasome activation and neuroinflammation. Increased levels of acetylated and phosphorylated HMGB1 may contribute to alcoholic neuroinflammation.
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Dora
authors.initials: D
authors.lastname: Lippai
authors.forename: Shashi
authors.initials: S
authors.lastname: Bala
authors.forename: Jan
authors.initials: J
authors.lastname: Petrasek
authors.forename: Timea
authors.initials: T
authors.lastname: Csak
authors.forename: Ivan
authors.initials: I
authors.lastname: Levin
authors.forename: Evelyn A
authors.initials: EA
authors.lastname: Kurt-Jones
authors.forename: Gyongyi
authors.initials: G
authors.lastname: Szabo
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000891:Anti-Infective Agents, Local / Q000633:toxicity; D051017:Apoptosis Regulatory Proteins; D015153:Blotting, Western; D001921:Brain / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000502:physiology*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000502:physiology*; D000431:Ethanol / Q000633:toxicity*; D005260:Female; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism; D047468:Immunoprecipitation; D058847:Inflammasomes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology; D053583:Interleukin-1beta / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000502:physiology*
chemical_list: D000891:Anti-Infective Agents, Local; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D016207:Cytokines; D003598:Cytoskeletal Proteins; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D058847:Inflammasomes; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D017472:Receptors, Interleukin-1; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D000431:Ethanol
keywords: CNS; HMGB1; MCP-1; TNF-α; cerebellum