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.
Highlights
Inflammasome activation has been implicated in various inflammatory diseases including post-ischaemic inflammation after stroke
We demonstrate that Bruton’s tyrosine kinase (BTK) is activated in infiltrating macrophages/ neutrophils in a brain ischaemia/reperfusion model, and that ibrutinib strongly protects against brain injury
Caspase-1 activation was significantly lower in the brain of BTK-deficient X-linked immunodeficiency (Xid) mice than in that of WT mice (Fig. 4f,g,h). These results suggest that BTK inhibition suppresses inflammasome activation and reduces caspase-1 activation and IL-1b secretion, promoting neural protection in the injured brain. Recently, multiple kinases such as PKC-d and PKR have been identified as regulators of inflammasome activation[21,22] and we have shown that the TAK1-JNK pathway is necessary for a caspase-recruitment domain (ASC) oligomerization induced by lysosome rupture[26]
Summary
Inflammasome activation has been implicated in various inflammatory diseases including post-ischaemic inflammation after stroke. IL-1b, caspase-1 and NLR family, pyrin domain containing 3 (NLRP3) have been reported to play critical roles in rodent models of ischaemic brain injury[12,13,14] and the IL-1b gene single-nucleotide polymorphism is reportedly associated with stroke[15]. We demonstrate that BTK is activated in infiltrating macrophages/ neutrophils in a brain ischaemia/reperfusion model, and that ibrutinib strongly protects against brain injury. These results may enhance our understanding of the mechanism underlying NLRP3 inflammasome activation and the effectiveness of BTK inhibitors for the treatment of acute inflammatory diseases including ischaemic stroke
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