{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:18:59Z","timestamp":1792790339275,"version":"4.5.0"},"posted":{"date-parts":[[2026,3,13]]},"group-title":"Neuroscience","reference-count":43,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T00:00:00Z","timestamp":1773360000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"NHMRC","award":["2024\/GNT2034754"],"award-info":[{"award-number":["2024\/GNT2034754"]}],"id":[{"id":"https:\/\/ror.org\/011kf5r70","id-type":"ROR","asserted-by":"crossref"}]},{"name":"NHMRC","award":["2017086"],"award-info":[{"award-number":["2017086"]}],"id":[{"id":"https:\/\/ror.org\/011kf5r70","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>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\u2013cell 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-\u03baB activation, NLRP3 inflammasome assembly and IL-1\u03b2 release. Together, these findings position E-selectin as an upstream regulator of IL-1\u03b2\u2013 dependent neuroinflammation in VIPN and identify selective targeting of E-selectin\u2013 mediated immune-neuron interactions as a potential preventative therapeutic strategy for chemotherapy-induced neuropathy.<\/jats:p>","DOI":"10.64898\/2026.03.10.710929","type":"posted-content","created":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T14:10:10Z","timestamp":1773411010000},"source":"Crossref","is-referenced-by-count":0,"title":["E-Selectin Orchestrates IL-1\u03b2\u2013Dependent Neuroinflammation via NLRP3 in Vincristine-Induced Neuropathy"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9401-1744","authenticated-orcid":false,"given":"Hana","family":"Starobova","sequence":"first","affiliation":[{"name":"Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ammar","family":"Alshammari","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikhil Nageshwar","family":"Inturi","sequence":"additional","affiliation":[{"name":"Department of Neuroscience and Center for Advanced Pain Studies, University of Texas at Dallas, Richardson TX 75080, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolette","family":"Tay","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Pharmaceutical Sciences, The University of Queensland, Woolloongabba, QLD, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svetlana","family":"Shatunova","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia"},{"name":"Mater Research Institute and Translational Research Institute, The University of Queensland, QLD, Australia, Translational Research Institute, Woolloongabba, QLD, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Lam","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quan","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marisol Mancilla","family":"Moreno","sequence":"additional","affiliation":[{"name":"Department of Neuroscience and Center for Advanced Pain Studies, University of Texas at Dallas, Richardson TX 75080, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0986-3630","authenticated-orcid":false,"given":"Diana","family":"Tavares-Ferreira","sequence":"additional","affiliation":[{"name":"Department of Neuroscience and Center for Advanced Pain Studies, University of Texas at Dallas, Richardson TX 75080, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Iseppon","sequence":"additional","affiliation":[{"name":"Experimental Neurology Unit, School of Medicine and Surgery, University of Milano-Bicocca, 20900, Monza, ITALY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia","family":"Rodriguez-Menendez","sequence":"additional","affiliation":[{"name":"Experimental Neurology Unit, School of Medicine and Surgery, University of Milano-Bicocca, 20900, Monza, ITALY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4281-4577","authenticated-orcid":false,"given":"Cristina","family":"Meregalli","sequence":"additional","affiliation":[{"name":"Experimental Neurology Unit, School of Medicine and Surgery, University of Milano-Bicocca, 20900, Monza, ITALY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brittany","family":"Hill","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larissa","family":"Labzin","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simranpreet","family":"Kaur","sequence":"additional","affiliation":[{"name":"Mater Research Institute and Translational Research Institute, The University of Queensland, QLD, Australia, Translational Research Institute, Woolloongabba, QLD, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darren L.","family":"Brown","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4128-2406","authenticated-orcid":false,"given":"Guido","family":"Cavaletti","sequence":"additional","affiliation":[{"name":"Experimental Neurology Unit, School of Medicine and Surgery, University of Milano-Bicocca, 20900, Monza, ITALY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6971-6221","authenticated-orcid":false,"given":"Theodore J.","family":"Price","sequence":"additional","affiliation":[{"name":"Department of Neuroscience and Center for Advanced Pain Studies, University of Texas at Dallas, Richardson TX 75080, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avril","family":"Robertson","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia"},{"name":"School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer L.","family":"Stow","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid G","family":"Winkler","sequence":"additional","affiliation":[{"name":"Mater Research Institute and Translational Research Institute, The University of Queensland, QLD, Australia, Translational Research Institute, Woolloongabba, QLD, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Vetter","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia"},{"name":"School of Pharmacy and Pharmaceutical Sciences, The University of Queensland, Woolloongabba, QLD, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026100304300518000_2026.03.10.710929v2.1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-04-1623"},{"key":"2026100304300518000_2026.03.10.710929v2.2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2010.30.1382"},{"key":"2026100304300518000_2026.03.10.710929v2.3","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2012.46.2309"},{"key":"2026100304300518000_2026.03.10.710929v2.4","doi-asserted-by":"crossref","unstructured":"Tay, N. et al. Chemotherapy-induced peripheral neuropathy in children and adolescent cancer patients. Frontiers in molecular biosciences 9 (2022).","DOI":"10.3389\/fmolb.2022.1015746"},{"key":"2026100304300518000_2026.03.10.710929v2.5","first-page":"2416","article-title":"Vincristine-induced peripheral neuropathy in pediatric cancer patients","volume":"6","year":"2016","journal-title":"American journal of cancer research"},{"key":"2026100304300518000_2026.03.10.710929v2.6","doi-asserted-by":"crossref","unstructured":"Starobova, H. & Vetter, I . Pathophysiology of chemotherapy-induced peripheral neuropathy. Frontiers in molecular neuroscience 10, 174 (2017).","DOI":"10.3389\/fnmol.2017.00174"},{"key":"2026100304300518000_2026.03.10.710929v2.7","doi-asserted-by":"publisher","DOI":"10.1172\/JCI71389"},{"key":"2026100304300518000_2026.03.10.710929v2.8","doi-asserted-by":"crossref","unstructured":"Starobova, H. et al. Vincristine-induced peripheral neuropathy is driven by canonical NLRP3 activation and IL-1\u03b2 release. Journal of Experimental Medicine 218 (2021).","DOI":"10.1084\/jem.20201452"},{"key":"2026100304300518000_2026.03.10.710929v2.9","doi-asserted-by":"crossref","first-page":"1878","DOI":"10.3389\/fimmu.2017.01878","article-title":"E-selectin ligands in the human mononuclear phagocyte system: implications for infection, inflammation, and immunotherapy","volume":"8","year":"2018","journal-title":"Frontiers in immunology"},{"key":"2026100304300518000_2026.03.10.710929v2.10","doi-asserted-by":"crossref","unstructured":"Jia, M. et al. Activation of NLRP3 inflammasome in peripheral nerve contributes to paclitaxel-induced neuropathic pain. Molecular pain 13, 1744806917719804 (2017).","DOI":"10.1177\/1744806917719804"},{"key":"2026100304300518000_2026.03.10.710929v2.11","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1007\/s10787-017-0401-9","article-title":"Pharmacological inhibition of the NLRP3 inflammasome as a potential target for multiple sclerosis induced central neuropathic pain","volume":"26","year":"2018","journal-title":"Inflammopharmacology"},{"key":"2026100304300518000_2026.03.10.710929v2.12","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3795-08.2008"},{"key":"2026100304300518000_2026.03.10.710929v2.13","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1038\/s41589-019-0277-7","article-title":"MCC950 directly targets the NLRP3 ATP-hydrolysis motif for inflammasome inhibition","volume":"15","year":"2019","journal-title":"Nature chemical biology"},{"key":"2026100304300518000_2026.03.10.710929v2.14","doi-asserted-by":"publisher","DOI":"10.1002\/hem3.70092"},{"key":"2026100304300518000_2026.03.10.710929v2.15","doi-asserted-by":"crossref","first-page":"2042","DOI":"10.1038\/s41467-020-15817-5","article-title":"Endothelial E-selectin inhibition improves acute myeloid leukaemia therapy by disrupting vascular niche-mediated chemoresistance","volume":"11","year":"2020","journal-title":"Nature communications"},{"key":"2026100304300518000_2026.03.10.710929v2.16","doi-asserted-by":"publisher","DOI":"10.1016\/J.AJPATH.2013.02.010"},{"key":"2026100304300518000_2026.03.10.710929v2.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.06.011"},{"key":"2026100304300518000_2026.03.10.710929v2.18","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2019.00653"},{"key":"2026100304300518000_2026.03.10.710929v2.19","doi-asserted-by":"publisher","DOI":"10.1002\/JLB.MA0318-112RR"},{"key":"2026100304300518000_2026.03.10.710929v2.20","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1110156109"},{"key":"2026100304300518000_2026.03.10.710929v2.21","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2969"},{"key":"2026100304300518000_2026.03.10.710929v2.22","doi-asserted-by":"publisher","DOI":"10.1124\/mol.118.113076"},{"key":"2026100304300518000_2026.03.10.710929v2.23","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abb8828"},{"key":"2026100304300518000_2026.03.10.710929v2.24","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000004031"},{"key":"2026100304300518000_2026.03.10.710929v2.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2025.110434"},{"key":"2026100304300518000_2026.03.10.710929v2.26","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20201452"},{"key":"2026100304300518000_2026.03.10.710929v2.27","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"2026100304300518000_2026.03.10.710929v2.28","doi-asserted-by":"publisher","DOI":"10.1093\/biostatistics\/kxw041"},{"key":"2026100304300518000_2026.03.10.710929v2.29","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab043"},{"key":"2026100304300518000_2026.03.10.710929v2.30","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adj9173"},{"key":"2026100304300518000_2026.03.10.710929v2.31","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21246-9"},{"key":"2026100304300518000_2026.03.10.710929v2.32","doi-asserted-by":"publisher","DOI":"10.1007\/BF00227662"},{"key":"2026100304300518000_2026.03.10.710929v2.33","doi-asserted-by":"publisher","DOI":"10.3390\/ijms231710063"},{"key":"2026100304300518000_2026.03.10.710929v2.34","first-page":"1","article-title":"A novel interaction between CX3CR1 and CCR2 signalling in monocytes constitutes an underlying mechanism for persistent vincristine-induced pain","volume":"15","year":"2018","journal-title":"Journal of neuroinflammation"},{"key":"2026100304300518000_2026.03.10.710929v2.35","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/j.jpain.2019.06.008","article-title":"Inflammatory and neuropathic gene expression signatures of chemotherapy-induced neuropathy induced by vincristine, cisplatin, and oxaliplatin in C57BL\/6J mice","volume":"21","year":"2020","journal-title":"The journal of pain"},{"key":"2026100304300518000_2026.03.10.710929v2.36","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-024-01857-2"},{"key":"2026100304300518000_2026.03.10.710929v2.37","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1111\/imcb.12447","article-title":"Adhesion to E-selectin primes macrophages for activation through AKT and mTOR","volume":"99","year":"2021","journal-title":"Immunology and Cell Biology"},{"key":"2026100304300518000_2026.03.10.710929v2.38","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1191\/1352458505ms1205oa","article-title":"Relapse rates and enhancing lesions in a phase II trial of natalizumab in multiple sclerosis","volume":"11","year":"2005","journal-title":"Multiple Sclerosis Journal"},{"key":"2026100304300518000_2026.03.10.710929v2.39","doi-asserted-by":"crossref","unstructured":"Shirani, A. & St\u00fcve, O . Natalizumab: perspectives from the bench to bedside. Cold Spring Harbor Perspectives in Medicine 8, a029066 (2018).","DOI":"10.1101\/cshperspect.a029066"},{"key":"2026100304300518000_2026.03.10.710929v2.40","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvad130"},{"key":"2026100304300518000_2026.03.10.710929v2.41","doi-asserted-by":"publisher","DOI":"10.1136\/spcare-2022-003815"},{"key":"2026100304300518000_2026.03.10.710929v2.42","doi-asserted-by":"publisher","DOI":"10.3109\/15419069809109147"},{"key":"2026100304300518000_2026.03.10.710929v2.43","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.112.24.4695"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.03.10.710929","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T11:30:17Z","timestamp":1791027017000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.03.10.710929"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,13]]},"references-count":43,"URL":"https:\/\/doi.org\/10.64898\/2026.03.10.710929","relation":{"has-version":[{"id-type":"doi","id":"10.7554\/eLife.111950.1","asserted-by":"object"}]},"subject":[],"published":{"date-parts":[[2026,3,13]]},"subtype":"preprint"}}