MIF-Mediated NLRP3 Inflammasome-Dependent Pyroptosis in Spinal Neurons and Microglial Polarization Facilitate Neuropathic Pain Progression.

Despite considerable advancements in therapeutic approaches, neuropathic pain remains a globally prevalent and challenging source of chronic suffering, underscoring the urgent demand for innovative treatment strategies. Here, we investigated the role of macrophage migration inhibitory factor (MIF) in neuropathic pain using a rodent model of chronic constriction injury (CCI) to the sciatic nerve, approved by the Ethical Committee of Animal Use and Care. Mechanical thresholds (von Frey hairs) and thermal latencies (hot plate) were measured, alongside spinal MIF expression, pyroptosis markers (e.g., GSDMD-N), and inflammatory cytokines (IL-1β, IL-6, and TNF-α). Our results showed that spinal MIF levels surged post-CCI, peaking on day 14 (p < 0.001), and drove microglial M1 polarization and inflammatory cytokine release (all p < 0.01). Notably, MIF activated the NLRP3 inflammasome, exacerbating neuronal pyroptosis (p < 0.01). These effects were mitigated by MIF inhibitor ISO-1 or NF-κB inhibitor PDTC, which reduced neuroinflammation and pain hypersensitivity. Collectively, this study reveals that MIF promotes NLRP3 inflammasome-mediated neuronal pyroptosis and microglial polarization via the NF-κB pathway, providing novel mechanistic insights into neuropathic pain alleviation through MIF inhibition.