E-Selectin Orchestrates IL-1β-Dependent Neuroinflammation via NLRP3 in Vincristine-Induced Neuropathy.

Vincristine-induced peripheral neuropathy (VIPN) is a frequent and dose-limiting complication of cancer therapy, yet the upstream mechanisms coupling vascular activation to neuroinflammation remain poorly defined. Here we identify the vascular leukocyte adhesion molecule E-selectin (CD62E) as a critical orchestrator of vincristine-induced neuropathy. Systematic interrogation of endothelial-expressed leukocyte cell adhesion molecules (CAMs) in a murine model of VIPN revealed that blockade of E-selectin, but not ICAM-1, PECAM-1 or P-selectin, completely prevented mechanical hypersensitivity and markedly reduced F4/80 immune cell accumulation in dorsal root ganglia (DRG) and peripheral nerves. Genetic deletion of E-selectin (Sele) conferred similar VIPN protection, despite the absence of structural intraepidermal or myelinated fibres loss, indicating a predominantly functional neuroimmune pathology. Spatial transcriptomics demonstrated that vincristine induces a conserved stress and neuroinflammation-associated transcriptional programme in DRG, with immune and stromal populations acting as dominant signalling hubs. Genetic or pharmacological perturbation of E-selectin did not abolish injury-associated pathways but redistributed cell-cell communication networks, reducing immune-cell dominance and reshaping interferon and metabolic signalling. Mechanistically, E-selectin exerted non-canonical effects beyond endothelial adhesion. Local recombinant E-selectin administration was sufficient to induce phagocyte-dependent mechanical hypersensitivity that was abolished in Fut4/7- (functional receptor) deficient mice. In macrophages, E-selectin adhesion mediated enhanced vincristine-driven NF-κB activation, NLRP3 inflammasome assembly and IL-1β release. Together, these findings position E-selectin as an upstream regulator of IL-1β- dependent neuroinflammation in VIPN and identify selective targeting of E-selectin- mediated immune-neuron interactions as a potential preventative therapeutic strategy for chemotherapy-induced neuropathy.