RRC ID 35703
Author Ito M, Shichita T, Okada M, Komine R, Noguchi Y, Yoshimura A, Morita R.
Title Bruton's tyrosine kinase is essential for NLRP3 inflammasome activation and contributes to ischaemic brain injury.
Journal Nat Commun
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.
Volume 6
Pages 7360
Published 2015-6-10
DOI 10.1038/ncomms8360
PII ncomms8360
PMID 26059659
PMC PMC4490404
MeSH Animals Brain Ischemia / metabolism* Carrier Proteins / metabolism* Inflammasomes / metabolism* Mice NLR Family, Pyrin Domain-Containing 3 Protein Protein Kinase Inhibitors / pharmacology Protein-Tyrosine Kinases / antagonists & inhibitors Protein-Tyrosine Kinases / metabolism*
IF 12.353
Times Cited 31
WOS Category IMMUNOLOGY
Resource
DNA material CSII-EF-MCS-IRES2-Venus (RDB04384) pCMV-VSV-G-RSV-Rev (RDB04393).