Neuronal NLRP3 inflammasome mediates spreading depolarization-evoked trigeminovascular activation.

This article investigates the role of the NLRP3 inflammasome in spreading depolarization (SD)-evoked cortical neuroinflammation and trigeminovascular activation, mechanisms implicated in migraine pathogenesis. The study demonstrates that SD induces opening of the pannexin 1 (PANX1) channel, leading to activation and assembly of the neuronal NLRP3 inflammasome within minutes, which triggers downstream inflammatory cascades including IL-1β release. Pharmacological inhibition or genetic ablation of Nlrp3 and Il1b attenuated SD-induced neuroinflammation and markers of trigeminovascular activation, such as middle meningeal artery dilation and calcitonin gene-related peptide expression. Additionally, multiple SDs activated microglia via the HMGB1–TLR2/4 signaling pathway, which in turn facilitated neuronal NLRP3-mediated inflammation, suggesting a neuron–microglia interplay in sustaining cortical inflammation. These findings highlight the importance of innate immune responses, particularly neuronal NLRP3 inflammasome activation and microglial involvement, in the neurobiology of migraine aura and headache.