A transient receptor potential vanilloid 1-dependent corneal-trigeminal neuroinflammatory circuit promotes corneal neuropathy

A transient receptor potential vanilloid 1-dependent corneal-trigeminal neuroinflammatory circuit promotes corneal neuropathy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article A transient receptor potential vanilloid 1-dependent corneal-trigeminal neuroinflammatory circuit promotes corneal neuropathy Manuela Pizzano, Alexia Vereertbrugghen, Jazmín Martínez, Juliana Bernatowiez, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6916662/v3 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 25 Feb, 2026 Read the published version in Experimental & Molecular Medicine → Version 3 posted 7 You are reading this latest preprint version Show more versions Abstract Corneal neurosensory abnormalities cause pain and discomfort in ocular surface disease, yet their pathophysiology is poorly understood. Here, we show that in a mouse dry eye model, ocular (over)activation of transient receptor potential vanilloid-1 (TRPV1) channels in response to tear deficiency and tissue damage promotes neuroinflammatory gene expression and macrophage reactivity in the trigeminal ganglion, where the cornea-innervating sensory neurons are located. This is accompanied by ocular surface macrophage activation, impaired corneal sensitivity to mechanical and non-TRPV1-mediated chemical stimulation, reduced corneal nerve density, and sensitization of ocular TRPV1 channels, thus establishing a vicious neurosensory cycle. Isolated corneal TRPV1 activation without ocular desiccation recapitulates macrophage reactivity, corneal nerve degeneration, and trigeminal neuroinflammation, whereas ocular substance P blockade reverts most of the TRPV1-driven corneal neurosensory abnormalities. Our study identifies a corneal-trigeminal axis that facilitates corneal neurosensory dysfunction and suggests potential targets for the treatment of ocular surface disease-associated corneal neuropathy. Health sciences/Pathogenesis/Inflammation/Chronic inflammation Biological sciences/Immunology/Neuroimmunology Biological sciences/Immunology/Mucosal immunology Biological sciences/Neuroscience/Neuroimmunology Health sciences/Diseases/Immunological disorders/Autoimmune diseases Full Text Additional Declarations There is no conflict of interest Supplementary Files SupplementalTableandFigures.pdf Supplemental Table and Figures 1-9 Cite Share Download PDF Status: Published Journal Publication published 25 Feb, 2026 Read the published version in Experimental & Molecular Medicine → Version 3 posted Editorial decision: revise 18 Nov, 2025 Review # 1 received at journal 17 Nov, 2025 Reviewer # 1 agreed at journal 02 Nov, 2025 Reviewers invited by journal 02 Nov, 2025 Submission checks completed at journal 02 Nov, 2025 Editor assigned by journal 31 Oct, 2025 First submitted to journal 31 Oct, 2025 You are reading this latest preprint version Show more versions Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6916662","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[{"code":1,"date":"2025-06-20 02:05:58","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research 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neuropathy","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"experimental-and-molecular-medicine","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"emm","sideBox":"Learn more about [Experimental \u0026 Molecular Medicine](http://www.nature.com/emm/)","snPcode":"12276","submissionUrl":"https://mts-emm.nature.com/cgi-bin/main.plex","title":"Experimental \u0026 Molecular Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature 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Here, we show that in a mouse dry eye model, ocular (over)activation of transient receptor potential vanilloid-1 (TRPV1) channels in response to tear deficiency and tissue damage promotes neuroinflammatory gene expression and macrophage reactivity in the trigeminal ganglion, where the cornea-innervating sensory neurons are located. This is accompanied by ocular surface macrophage activation, impaired corneal sensitivity to mechanical and non-TRPV1-mediated chemical stimulation, reduced corneal nerve density, and sensitization of ocular TRPV1 channels, thus establishing a vicious neurosensory cycle. Isolated corneal TRPV1 activation without ocular desiccation recapitulates macrophage reactivity, corneal nerve degeneration, and trigeminal neuroinflammation, whereas ocular substance P blockade reverts most of the TRPV1-driven corneal neurosensory abnormalities. Our study identifies a corneal-trigeminal axis that facilitates corneal neurosensory dysfunction and suggests potential targets for the treatment of ocular surface disease-associated corneal neuropathy.","manuscriptTitle":"A transient receptor potential vanilloid 1-dependent corneal-trigeminal neuroinflammatory circuit promotes corneal neuropathy","msid":"","msnumber":"","nonDraftVersions":[{"code":3,"date":"2025-11-04 16:02:17","doi":"10.21203/rs.3.rs-6916662/v3","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2025-11-18T06:32:40+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2025-11-17T15:24:13+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-11-03T03:09:52+00:00","index":1,"fulltext":"This content is not 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