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

Starobova, H.; Alshammari, A.; Inturi, N. N.; Tay, N.; Shatunova, S.; Lam, A.; Nguyen, Q.; Moreno, M. M.; Tavares-Ferreira, D.; Iseppon, F.; Rodriguez-Menendez, V.; Meregalli, C.; Hill, B.; Labzin, L.; Kaur, S.; Brown, D. L.; Cavaletti, G.; Price, T. J.; Robertson, A.; Pettit, A.; Stow, J. L.; Winkler, I. G.; Vetter, I.

doi:10.64898/2026.03.10.710929

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bioRxiv · 10.64898/2026.03.10.710929

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

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Abstract

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 E-selectin as a critical orchestrator of vincristine-induced neuropathy. Systematic interrogation of endothelial adhesion molecules 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 and peripheral nerves. Genetic deletion of E-selectin conferred equivalent protection, despite the absence of structural loss of intraepidermal or myelinated fibres, indicating a predominantly functional neuroimmune pathology. Spatial transcriptomics demonstrated that vincristine induces a conserved stress and neuroinflammation-associated transcriptional programme in dorsal root ganglia, 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 states without inducing Sele expression. Mechanistically, E-selectin exerted non-canonical effects beyond endothelial adhesion. Local E-selectin administration was sufficient to induce macrophage-dependent mechanical hypersensitivity that was abolished in Fut4/7-deficient mice and following phagocyte depletion. In macrophages, E-selectin enhanced vincristine-driven NF-{kappa}B activation, NLRP3 inflammasome assembly and IL-1{beta} release. Together, these findings position E-selectin as an upstream regulator of IL-1{beta}-dependent neuroinflammation in VIPN and identify selective targeting of E-selectin-mediated immune-neuron interactions as a therapeutic strategy for chemotherapy-induced neuropathy.

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Starobova, H., Alshammari, A., Inturi, N. N., Tay, N., Shatunova, S., Lam, A., Nguyen, Q., Moreno, M. M., Tavares-Ferreira, D., Iseppon, F., Rodriguez-Menendez, V., Meregalli, C., Hill, B., Labzin, L., Kaur, S., Brown, D. L., Cavaletti, G., Price, T. J., Robertson, A., Pettit, A., Stow, J. L., Winkler, I. G., Vetter, I.. 2026-03-13. E-Selectin Orchestrates IL-1B-Dependent Neuroinflammation via NLRP3 in Vincristine-Induced Neuropathy. https://doi.org/10.64898/2026.03.10.710929

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