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Innate immune signaling pathways are essential mediators of inflammation and repair following myelin injury. Inflammasome activation has recently been implicated as a driver of myelin injury in multiple sclerosis (MS) and its animal models, although the regulation and contributions of inflammasome activation in the demyelinated central nervous system (CNS) are not completely understood. Herein, we investigated the NLRP3 (NBD‐, LRR‐ and pyrin domain‐containing protein 3) inflammasome and its endogenous regulator microRNA‐223‐3p within the demyelinated CNS in both MS and an animal model of focal demyelination. We observed that NLRP3 inflammasome components and microRNA‐223‐3p were upregulated at sites of myelin injury within activated macrophages and microglia. Both microRNA‐223‐3p and a small‐molecule NLRP3 inhibitor, MCC950, suppressed inflammasome activation in …