Astrocyte-microglia IL-3-IL-3Rα signaling drives JAK2/STAT5-dependent neuroinflammation and neurodegeneration after status epilepticus.

Abstract

Epilepsy is a prevalent neurological disorder characterized by recurrent seizures, chronic neuroinflammation, and progressive neurodegeneration. While neuronal hyperexcitability has been extensively studied, the contribution of glial interactions-particularly between astrocytes and microglia-remains poorly understood. Here, we identify the astrocyte-microglia IL-3-IL-3Rα signaling axis as a critical mediator of neuroinflammatory and neurodegenerative responses following status epilepticus (SE). In a pilocarpine-induced SE mouse model, we observed increased expression of interleukin-3 (IL-3) in astrocytes and its receptor IL-3Rα in microglia within the hippocampus. In vitro, IL-3 stimulation induced robust production of pro-inflammatory cytokines (IL-1β, TNF-α, and iNOS) in BV-2 microglia via the JAK2/STAT5 signaling pathway, an effect significantly attenuated by the selective JAK2 inhibitor AG490. In vivo, AG490 treatment reduced seizure severity, suppressed epileptiform EEG discharges, alleviated hippocampal inflammation, and importantly, mitigated SE-induced neuronal loss and nuclear damage in the hippocampus. Collectively, our data demonstrate that the IL-3-IL-3Rα-JAK2/STAT5 signaling axis, while known in other contexts, is a critical mediator of glial communication and pathology in the post-seizure brain, offering a promising target for therapeutic intervention in epilepsy.