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

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  • Minako Ito

    (Keio University School of Medicine
    Japan Science and Technology Agency (JST), CREST)

  • Takashi Shichita

    (Keio University School of Medicine
    Japan Science and Technology Agency (JST), CREST
    PRESTO (Precursory Research for Embryonic Science and Technology))

  • Masahiro Okada

    (Keio University School of Medicine
    Japan Science and Technology Agency (JST), CREST)

  • Ritsuko Komine

    (Keio University School of Medicine
    Japan Science and Technology Agency (JST), CREST)

  • Yoshiko Noguchi

    (Keio University School of Medicine
    Japan Science and Technology Agency (JST), CREST)

  • Akihiko Yoshimura

    (Keio University School of Medicine
    Japan Science and Technology Agency (JST), CREST)

  • Rimpei Morita

    (Keio University School of Medicine
    Japan Science and Technology Agency (JST), CREST)

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.

Suggested Citation

  • Minako Ito & Takashi Shichita & Masahiro Okada & Ritsuko Komine & Yoshiko Noguchi & Akihiko Yoshimura & Rimpei Morita, 2015. "Bruton’s tyrosine kinase is essential for NLRP3 inflammasome activation and contributes to ischaemic brain injury," Nature Communications, Nature, vol. 6(1), pages 1-11, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8360
    DOI: 10.1038/ncomms8360
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