Micheliolide interferes PKM2-P65 interaction and inhibits inflammasome activation in macrophage after ischemic stroke

Confronting post-stroke neural inflammation is regarded as a promising therapeutic strategy for cerebral ischemia. Macrophage inflammasome activation plays a vital role in driving neural inflammation, and thus directly impacts stroke outcomes. Micheliolide (MCL), a newly discovered modifier of macrophage function, mechanistically suppresses NLRP3 macrophage signaling. The purpose of the present study was to evaluate the role of inflammasome suppression in MCL-based treatment for stroke. Decreased lesion volumes and improved neurological function in mice receiving MCL treatment were measured at both 3- and 14- day intervals after stroke. PKM2 (Pyruvate Kinase M2) was identified as the direct target of MCL that was found to efficiently suppress inflammasome activation and downregulate NF-κB (NLR family pyrin domain containing 3) signaling. P65 (subunit of NF-κB) binding of PKM2 increases during inflammasome induction and MCL treatment interfered with this interaction. In conclusion, MCL interferes with the PKM2-NF-κB interaction during inflammasome activation and ameliorates post-stroke inflammation, demonstrating its potential in acute ischemic stroke treatment.