Bruton's tyrosine kinase is essential for NLRP3 inflammasome activation and contributes to ischaemic brain injury.
Bruton's tyrosine kinase is essential for NLRP3 inflammasome activation and contributes to ischaemic brain injury.
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DOI：
10.1038/ncomms8360
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发表时间：
2015-06-10
影响因子：
16.6
通讯作者：
Morita, Rimpei
中科院分区：
文献类型：
--
作者：
Ito, Minako;Shichita, Takashi;Okada, Masahiro;Komine, Ritsuko;Noguchi, Yoshiko;Yoshimura, Akihiko;Morita, Rimpei
炎性小体激活与多种炎性疾病有关，包括中风后的缺血后炎症。炎性小体介导半胱天冬酶-1的活化，其随后诱导促炎性细胞因子如IL-1β和IL-18的分泌，以及称为焦亡的细胞死亡形式。在这项研究中，我们报告说，布鲁顿的酪氨酸激酶（BTK）是一个重要组成部分的NLRP 3炎性小体，其中BTK物理相互作用与ASC和NLRP 3。通过药理学或遗传手段抑制BTK严重损害NLRP 3炎性体的活化。FDA批准的BTK抑制剂伊布替尼（PCI-32765）有效抑制小鼠脑缺血/再灌注模型中的梗死体积增长和神经损伤。伊曲替尼通过抑制缺血性脑梗死区浸润性巨噬细胞和中性粒细胞中的半胱天冬酶-1活化来抑制IL-1β的成熟。我们的研究表明，BTK是NLRP 3炎性体激活所必需的，并可能成为缺血性卒中的有效治疗靶点。 炎性体的激活导致几种病理。在这里，作者表明，布鲁顿的酪氨酸激酶是NLRP 3炎性体激活所必需的，并且用FDA批准的抑制剂伊曲替尼阻断它可以限制缺血性中风小鼠模型的组织损伤。
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. Activation of inflammasome contributes to several pathologies. Here, the authors show that Bruton's tyrosine kinase is essential for NLRP3 inflammasome activation, and that blocking it with the FDA-approved inhibitor ibrutinib limits tissue damage in a mouse model of ischaemic stroke.
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