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Type 1 interferon (IFN) signalling plays a major role in SSc disease progression. The cytokine TGF-\u03b2 has been extensively shown to be a major driver of fibrosis but its role in the induction of the type 1 interferon response is poorly understood.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>Type 1 IFN signalling was activated in keratinocytes using a range of agonists, IFN2\u03b1, Poly I:C, Poly dA:dT, LPS and TGF-\u03b2. CLIC4 activity was inhibited with the small molecule chloride channel inhibitors NPPB, IAA:94 and siRNA specific to CLIC4. Conditioned media collected from Healthy and SSc dermal fibroblasts was used to stimulate keratinocytes.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>TGF-\u03b2 stimulation induces a type 1 IFN response in keratinocytes, dependent on the chloride intracellular channel 4 (CLIC4). Inhibition of CLIC4 via small molecule inhibitors or siRNA attenuates TGF-\u03b2 mediated activation of Signal Transducer and Activator of Transcription 1 (STAT1) in keratinocytes. Further analysis revealed SSc dermal fibroblasts induce a type 1 IFN response in keratinocytes in part through a TGF\u03b2R1-CLIC4 axis.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>This study shows the ability of CLIC4 to enhance TGF-\u03b2 signalling is essential for aberrant type 1 interferon signalling in SSc skin.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s13075-025-03632-6","type":"journal-article","created":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T10:24:39Z","timestamp":1756722279000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Transforming growth factor beta (TGF-\u03b2) induces type 1 interferon signalling in systemic sclerosis keratinocytes through the chloride intracellular channel 4 (CLIC4)"],"prefix":"10.1186","volume":"27","author":[{"given":"Christopher W.","family":"Wasson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie L.","family":"Dibb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bego\u00f1a","family":"Caballero-Ruiz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ifeoluwa E.","family":"Bamigbola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Di Donato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva M.","family":"Madourie-Clavane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Wells","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vishal","family":"Kakkar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrico","family":"De Lorenzis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Bryon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Derrett-Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher P.","family":"Denton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasser","family":"El-Sherbiny","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul J.","family":"Meakin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca L.","family":"Ross","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Del Galdo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,1]]},"reference":[{"issue":"7","key":"3632_CR1","doi-asserted-by":"publisher","first-page":"920","DOI":"10.1136\/annrheumdis-2020-218439","volume":"80","author":"RL Ross","year":"2021","unstructured":"Ross RL, Corinaldesi C, Migneco G, Carr IM, Antanaviciute A, Wasson CW, et al. 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All participants provided written informed consent to participate in this study. Informed consent procedure was approved by NRES-011NE to FDG by the University of Leeds. For all in vivo mouse experiments there was strict adherence to institutional guidelines was practiced, and full local ethics committee approval through the UCL Animal Welfare and Ethical Review Body (AWERB) and appropriate Home Office Project and Personal license through CPD.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"CC BY-NC-ND: The article can be shared for non-commercial purposes as long as the authors are credited. Permission is needed for commercial re-use or sharing adapted and derivative versions.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"173"}}