CYLD Limits Neutrophil-Driven Psoriatic Inflammation

CYLD Limits Neutrophil-Driven Psoriatic Inflammation | 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 Research Article CYLD Limits Neutrophil-Driven Psoriatic Inflammation Zhenzong Fa, Zeping Huang, Yi Shang, Yang Yang, Qun Xie, Runping Yang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7849804/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 20 Jan, 2026 Read the published version in Inflammation → Version 1 posted 8 You are reading this latest preprint version Abstract Despite the well-recognized role of the deubiquitinase CYLD in the pathogenesis of tumors and certain inflammatory diseases, its specific function and regulatory mechanisms in psoriasis remain unclear; thus, we first analyzed CYLD expression differences between psoriatic patients and healthy controls using skin samples from the GEO database and validated its expression dynamics in an imiquimod (IMQ)-induced mouse model, then systematically evaluated the effects of CYLD deficiency on psoriasiform inflammation through histopathology, immunohistochemistry, RNA sequencing, and immunofluorescence analyses using Cyld knockout ( Cyld −/− ) mice, and employed bioinformatics approaches including CIBERSORT and Weighted Gene Co-expression Network Analysis (WGCNA) to further explore the associations between CYLD and neutrophil-related pathways and genes, with results showing that CYLD expression was significantly upregulated in lesional skin of psoriasis patients, Cyld −/− mice displayed more severe psoriasiform symptoms (enhanced epidermal thickening, increased neutrophil infiltration, significantly augmented formation of neutrophil extracellular traps [NETs]), CYLD deficiency led to excessive activation of the NF-κB signaling pathway and upregulated expression of various pro-inflammatory cytokines and chemokines, and bioinformatics analyses confirmed CYLD was closely associated with pathways related to neutrophil migration and activation, leading to the conclusion that CYLD plays a crucial negative regulatory role in psoriasis by inhibiting NF-κB-mediated neutrophil activation and NETs formation, so targeted activation of CYLD may represent a promising novel therapeutic strategy for psoriasis. Psoriasis CYLD Neutrophil Neutrophil extracellular traps. Full Text Additional Declarations No competing interests reported. Supplementary Files SupplementaryMaterials.docx Fig.S1OriginalimagesofFig.1D.docx Fig.S2OriginalimagesofFig9.docx Cite Share Download PDF Status: Published Journal Publication published 20 Jan, 2026 Read the published version in Inflammation → Version 1 posted Editorial decision: Revision requested 09 Dec, 2025 Reviews received at journal 09 Dec, 2025 Reviewers agreed at journal 09 Dec, 2025 Reviews received at journal 02 Dec, 2025 Reviewers agreed at journal 18 Nov, 2025 Reviewers invited by journal 21 Oct, 2025 Submission checks completed at journal 19 Oct, 2025 First submitted to journal 18 Oct, 2025 You are reading this latest preprint version 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. 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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-7849804","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":533811563,"identity":"574f1c63-4c3d-4332-a249-971a808da566","order_by":0,"name":"Zhenzong Fa","email":"","orcid":"","institution":"Department of Dermatology, the Sixth Medical Center, Chinese PLA General Hospital,100048","correspondingAuthor":false,"prefix":"","firstName":"Zhenzong","middleName":"","lastName":"Fa","suffix":""},{"id":533811565,"identity":"76e32e96-0b24-4d3f-bbc7-e12450c64cab","order_by":1,"name":"Zeping 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Inflammation","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"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":"inflammation","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ifla","sideBox":"Learn more about [Inflammation](https://www.springer.com/journal/10753)","snPcode":"10753","submissionUrl":"https://submission.nature.com/new-submission/10753/3","title":"Inflammation","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Psoriasis, CYLD, Neutrophil, Neutrophil extracellular traps.","lastPublishedDoi":"10.21203/rs.3.rs-7849804/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7849804/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eDespite the well-recognized role of the deubiquitinase CYLD in the pathogenesis of tumors and certain inflammatory diseases, its specific function and regulatory mechanisms in psoriasis remain unclear; thus, we first analyzed CYLD expression differences between psoriatic patients and healthy controls using skin samples from the GEO database and validated its expression dynamics in an imiquimod (IMQ)-induced mouse model, then systematically evaluated the effects of CYLD deficiency on psoriasiform inflammation through histopathology, immunohistochemistry, RNA sequencing, and immunofluorescence analyses using Cyld knockout (\u003cem\u003eCyld\u003c/em\u003e\u003csup\u003e\u003cem\u003e\u0026minus;/\u0026minus;\u003c/em\u003e\u003c/sup\u003e) mice, and employed bioinformatics approaches including CIBERSORT and Weighted Gene Co-expression Network Analysis (WGCNA) to further explore the associations between CYLD and neutrophil-related pathways and genes, with results showing that CYLD expression was significantly upregulated in lesional skin of psoriasis patients, \u003cem\u003eCyld\u003c/em\u003e\u003csup\u003e\u003cem\u003e\u0026minus;/\u0026minus;\u003c/em\u003e\u003c/sup\u003e mice displayed more severe psoriasiform symptoms (enhanced epidermal thickening, increased neutrophil infiltration, significantly augmented formation of neutrophil extracellular traps [NETs]), CYLD deficiency led to excessive activation of the NF-κB signaling pathway and upregulated expression of various pro-inflammatory cytokines and chemokines, and bioinformatics analyses confirmed CYLD was closely associated with pathways related to neutrophil migration and activation, leading to the conclusion that CYLD plays a crucial negative regulatory role in psoriasis by inhibiting NF-κB-mediated neutrophil activation and NETs formation, so targeted activation of CYLD may represent a promising novel therapeutic strategy for psoriasis.\u003c/p\u003e","manuscriptTitle":"CYLD Limits Neutrophil-Driven Psoriatic Inflammation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-31 07:59:55","doi":"10.21203/rs.3.rs-7849804/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision 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