Brown, D. L. | Search bioRxiv

bioRxiv2026

E-Selectin Orchestrates IL-1B-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 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.

neuroscience↗

bioRxiv2024

Macrophage migration-dependent retraction fibers and migrasomes - a structural basis for spatiotemporal cytokine secretion.

Migrating cells leave behind trails of matrix-bound retraction fibers and migrasomes, but their cell-specific physiological functions are largely unknown. We comprehensively characterize retraction fibers and migrasomes of migrating macrophages in mouse and zebrafish in vitro and in vivo models. These structures share common and macrophage-centric components of tetraspanin enriched microdomains (TEMs) including tetraspanin 4 (TSPAN4), the integrin CD11b and the pTRAP, SCIMP; like TSPAN4, we show that SCIMP expression modulates retraction fiber and migrasome formation. In immune-activated migrating macrophages, rear-positioned recycling endosomes regulate the secretory trafficking of newly synthesized inflammatory cytokines into retraction fibers and migrasomes. Transmembrane TNF is delivered via SNARE-mediated carriers to the cell surface and to the surfaces of both retraction fibers and migrasomes, from where it can be released. Retraction fibers are thus newly identified here as cytokine secretion sites, and along with migrasomes they allow migrating macrophages to secrete more cytokine compared to stationary cells. Whereas cytokine secretion has been viewed as a process of ad hoc diffusion, instead, we reveal a new mechanism of migration-dependent, localized deposition and spatiotemporal release of bioactive cytokines from RFs and migrasomes. Cytokine deployment is thus organized in a constrained manner facilitating direct influence on local inflammatory responses.

cell biology↗