Bruton’s tyrosine kinase is essential for NLRP3 inflammasome activation and contributes to ischaemic brain injury

Minako Ito, Takashi Shichita, Masahiro Okada, Ritsuko Komine, Yoshiko Noguchi, Akihiko Yoshimura () and Rimpei Morita ()
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Minako Ito: Keio University School of Medicine
Takashi Shichita: Keio University School of Medicine
Masahiro Okada: Keio University School of Medicine
Ritsuko Komine: Keio University School of Medicine
Yoshiko Noguchi: Keio University School of Medicine
Akihiko Yoshimura: Keio University School of Medicine
Rimpei Morita: Keio University School of Medicine

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8360

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