title: Bruton's tyrosine kinase is essential for NLRP3 inflammasome activation and contributes to ischaemic brain injury.
abstract: Inflammasome activation has been implicated in various inflammatory diseases including post-ischaemic inflammation after stroke. Inflammasomes mediate activation of caspase-1, which subsequently induces secretion of pro-inflammatory cytokines such as IL-1β and IL-18, as well as a form of cell death called pyroptosis. In this study, we report that Bruton's tyrosine kinase (BTK) is an essential component of the NLRP3 inflammasome, in which BTK physically interacts with ASC and NLRP3. Inhibition of BTK by pharmacological or genetic means severely impairs activation of the NLRP3 inflammasome. The FDA-approved BTK inhibitor ibrutinib (PCI-32765) efficiently suppresses infarct volume growth and neurological damage in a brain ischaemia/reperfusion model in mice. Ibrutinib inhibits maturation of IL-1β by suppressing caspase-1 activation in infiltrating macrophages and neutrophils in the infarcted area of ischaemic brain. Our study indicates that BTK is essential for NLRP3 inflammasome activation and could be a potent therapeutic target in ischaemic stroke.
authors.affiliation: 1] Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan [2] Japan Science and Technology Agency (JST), CREST, Chiyoda-ku, Tokyo 102-0075, Japan.
authors.forename: Minako
authors.initials: M
authors.lastname: Ito
authors.affiliation: 1] Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan [2] Japan Science and Technology Agency (JST), CREST, Chiyoda-ku, Tokyo 102-0075, Japan [3] PRESTO (Precursory Research for Embryonic Science and Technology), Chiyoda-ku, Tokyo 102-0075, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Shichita
authors.affiliation: 1] Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan [2] Japan Science and Technology Agency (JST), CREST, Chiyoda-ku, Tokyo 102-0075, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Okada
authors.affiliation: 1] Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan [2] Japan Science and Technology Agency (JST), CREST, Chiyoda-ku, Tokyo 102-0075, Japan.
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Komine
authors.affiliation: 1] Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan [2] Japan Science and Technology Agency (JST), CREST, Chiyoda-ku, Tokyo 102-0075, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Noguchi
authors.affiliation: 1] Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan [2] Japan Science and Technology Agency (JST), CREST, Chiyoda-ku, Tokyo 102-0075, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
authors.affiliation: 1] Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan [2] Japan Science and Technology Agency (JST), CREST, Chiyoda-ku, Tokyo 102-0075, Japan.
authors.forename: Rimpei
authors.initials: R
authors.lastname: Morita
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D058847:Inflammasomes / Q000378:metabolism*; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse