Abstract

Chronic pain acts as a potent driver of progressive cognitive impairment. Although microglial hyperactivation serves as a pivotal mechanistic bridge in this comorbidity, the intracellular molecular cascades coupling persistent nociception to cognitive decline remain largely elusive. Here, we identify a previously unrecognized microglial secretome remodeling axis, governed by CX3CL1-CX3CR1 signaling, that drives pain-associated cognitive impairment. Clinically, elevated cerebrospinal fluid (CSF) CX3CL1 correlates strongly with cognitive impairment in chronic pain patients. In murine models, pharmacological blockade of the microglial CX3CL1-CX3CR1 signaling attenuated chronic pain-induced memory deficits. Mechanistically, aberrant CX3CL1-CX3CR1 activation triggers a sequential p38 MAPK-NF-κB cascade to upregulate the kinesin motor KIFC2. This KIFC2 surge fundamentally reprograms microglial vesicular trafficking, driving the massive release of IL-17-enriched small exosomes (<100 nm) that subsequently induce synaptic deterioration and neuronal apoptosis manifested by PSD95 degradation, caspase-3 cleavage, and compromised cell viability. Crucially, this microglial p38 MAPK-NF-κB-KIFC2 cascade hyperactivation was validated in situ within the hippocampal slices of chronic pain models. Collectively, our findings delineate a comprehensive cascade spanning from receptor hyperactivation to KIFC2-dependent exosomal remodeling, elucidating a novel mechanism of microglia-mediated neurotoxicity. Targeting this CX3CL1-KIFC2 exosomal axis offers a potential therapeutic strategy to uncouple chronic pain from its debilitating cognitive comorbidities.