{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T01:38:55Z","timestamp":1792546735546,"version":"4.5.0"},"reference-count":0,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T00:00:00Z","timestamp":1792454400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T00:00:00Z","timestamp":1792454400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"abstract":"<jats:sec>\n                    <jats:title>\n                      \ufeff\n                      <jats:bold>Objective<\/jats:bold>\n                    <\/jats:title>\n                    <jats:p>\n                      We previously showed that Semaphorin4A (Sema4A) is elevated in patients with systemic sclerosis (SSc) and promotes inflammation and fibrosis\n                      <jats:italic>in vitro<\/jats:italic>\n                      . Here, we examined the effect of Sema4A neutralization\n                      <jats:italic>in vivo<\/jats:italic>\n                      and in 3D fibrosis models.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Sema4A plasma levels were measured by ELISA in healthy controls (n=31) and patients with SSc (n=30). In the bleomycin SSc\u2010model, mice were treated with an anti\u2010Sema4A neutralizing antibody or its respective isotype control (n=6\u20107). The 3D fibrosis models, consisting of collagen hydrogel, dermal fibroblasts, and peripheral blood mononuclear cells, were stimulated with recombinant Sema4A, rapamycin, or antibodies neutralizing Sema4A, PlexinD1, PlexinB2, Neuropilin\u20101 or their respective isotype controls (n=6\u201010). Collagen content was determined by trichrome staining and hydroxyproline assay. Gene expression was determined by RT\u2010qPCR and obtained from GEO\u2010NCBI expression arrays, while protein expression by immunohistochemistry, immunoblotting and flow cytometry.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Circulating Sema4A was elevated in patients with SSc (p&lt;0.0001), while Sema4A receptors were elevated in SSc skin and lung (p ranged from &lt;0.05 to 0.0001). Anti\u2010Sema4A administration significantly reduced skin and lung collagen content in bleomycin\u2010treated mice (p&lt;0.01), as well as the expression of extracellular matrix components, fibrotic and inflammatory mediators, and immune cell infiltration. In the 3D models, SSc serum and SSc PBMCs induced cell contraction, which was drastically abrogated by blocking Sema4A (p&lt;0.01). This effect was associated with reduced expression of fibrotic mediators and attenuated mTORC1 pathway activation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>We confirmed the pro\u2010fibrotic and pro\u2010inflammatory role of Sema4A, postulating Sema4A neutralization as a novel approach for the treatment of SSc.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/art.70374","type":"journal-article","created":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T01:06:05Z","timestamp":1792544765000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Sema4A neutralization reduces fibrosis and inflammation in a mouse model of systemic sclerosis and a 3D model of immunity\u2010driven fibrosis"],"prefix":"10.1002","author":[{"given":"Jaime","family":"Marty","sequence":"first","affiliation":[{"name":"Rheumatology &amp; Immuno\u2010mediated Diseases Research Group (IRIDIS) Galicia Sur Health Research Institute (IIS Galicia Sur) SERGAS\u2010UVIGO  Vigo Spain"},{"name":"Department of Rheumatology University Hospital Complex of Vigo  Vigo Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2055-8426","authenticated-orcid":false,"given":"Sara","family":"Martinez\u2010Ramos","sequence":"additional","affiliation":[{"name":"Rheumatology &amp; Immuno\u2010mediated Diseases Research Group (IRIDIS) Galicia Sur Health Research Institute (IIS Galicia Sur) SERGAS\u2010UVIGO  Vigo Spain"},{"name":"Department of Rheumatology University Hospital Complex of Vigo  Vigo Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Rafael\u2010Vidal","sequence":"additional","affiliation":[{"name":"Rheumatology &amp; Immuno\u2010mediated Diseases Research Group (IRIDIS) Galicia Sur Health Research Institute (IIS Galicia Sur) SERGAS\u2010UVIGO  Vigo Spain"},{"name":"Department of Rheumatology University Hospital Complex of Vigo  Vigo Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz","family":"Malvar\u2010Fern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Rheumatology &amp; Immuno\u2010mediated Diseases Research Group (IRIDIS) Galicia Sur Health Research Institute (IIS Galicia Sur) SERGAS\u2010UVIGO  Vigo Spain"},{"name":"Department of Rheumatology University Hospital Complex of Vigo  Vigo Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiago","family":"Carvalheiro","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht University of Utrecht  Utrecht The Netherlands"},{"name":"Center for Translational Immunology, University Medical Center Utrecht University of Utrecht  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralph G.","family":"Tieland","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht University of Utrecht  Utrecht The Netherlands"},{"name":"Center for Translational Immunology, University Medical Center Utrecht University of Utrecht  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ines","family":"Ramos","sequence":"additional","affiliation":[{"name":"Center for Translational Immunology, University Medical Center Utrecht University of Utrecht  Utrecht The Netherlands"},{"name":"Oncode Institute  Utrecht The Netherlands"},{"name":"Champalimaud Foundation, Champalimaud Centre for the Unknown, Champalimaud Research, Physiology and Cancer Programme  Lisbon Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wiola","family":"Marut","sequence":"additional","affiliation":[{"name":"Center for Translational Immunology, University Medical Center Utrecht University of Utrecht  Utrecht The Netherlands"},{"name":"Winclove Probiotics  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Pinheiro\u2010Lopes","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht University of Utrecht  Utrecht The Netherlands"},{"name":"Center for Translational Immunology, University Medical Center Utrecht University of Utrecht  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Argibay","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine University Hospital Complex of Vigo  Vigo Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brenda","family":"Maure","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine University Hospital Complex of Vigo  Vigo Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caritina","family":"V\u00e1zquez\u2010Tri\u00f1anes","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine University Hospital Complex of Vigo  Vigo Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nair","family":"P\u00e9rez G\u00f3mez","sequence":"additional","affiliation":[{"name":"Rheumatology &amp; Immuno\u2010mediated Diseases Research Group (IRIDIS) Galicia Sur Health Research Institute (IIS Galicia Sur) SERGAS\u2010UVIGO  Vigo Spain"},{"name":"Department of Rheumatology University Hospital Complex of Vigo  Vigo Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Fern\u00e1ndez\u2010Fern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Department of Rheumatology University Hospital Complex of Vigo  Vigo Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Vila","sequence":"additional","affiliation":[{"name":"Rheumatology &amp; Immuno\u2010mediated Diseases Research Group (IRIDIS) Galicia Sur Health Research Institute (IIS Galicia Sur) SERGAS\u2010UVIGO  Vigo Spain"},{"name":"Department of Rheumatology University Hospital Complex of Vigo  Vigo Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Coral","family":"Mouri\u00f1o","sequence":"additional","affiliation":[{"name":"Rheumatology &amp; Immuno\u2010mediated Diseases Research Group (IRIDIS) Galicia Sur Health Research Institute (IIS Galicia Sur) SERGAS\u2010UVIGO  Vigo Spain"},{"name":"Department of Rheumatology University Hospital Complex of Vigo  Vigo Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4054-0290","authenticated-orcid":false,"given":"Rogier M","family":"Thurlings","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Radboudumc  Nijmegen the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arjan","family":"van Caam","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Radboudumc  Nijmegen the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Rivera","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine University Hospital Complex of Vigo  Vigo Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3461-3537","authenticated-orcid":false,"given":"Jos\u00e9 Mar\u00eda","family":"Pego\u2010Reigosa","sequence":"additional","affiliation":[{"name":"Rheumatology &amp; Immuno\u2010mediated Diseases Research Group (IRIDIS) Galicia Sur Health Research Institute (IIS Galicia Sur) SERGAS\u2010UVIGO  Vigo Spain"},{"name":"Department of Rheumatology University Hospital Complex of Vigo  Vigo Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy R.","family":"Radstake","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht University of Utrecht  Utrecht The Netherlands"},{"name":"Center for Translational Immunology, University Medical Center Utrecht University of Utrecht  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5902-2699","authenticated-orcid":false,"given":"Samuel","family":"Garcia","sequence":"additional","affiliation":[{"name":"Rheumatology &amp; Immuno\u2010mediated Diseases Research Group (IRIDIS) Galicia Sur Health Research Institute (IIS Galicia Sur) SERGAS\u2010UVIGO  Vigo Spain"},{"name":"Department of Rheumatology University Hospital Complex of Vigo  Vigo Spain"},{"name":"Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht University of Utrecht  Utrecht The Netherlands"},{"name":"Center for Translational Immunology, University Medical Center Utrecht University of Utrecht  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,20]]},"container-title":["Arthritis &amp; Rheumatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.70374","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.70374","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T01:06:06Z","timestamp":1792544766000},"score":1,"resource":{"primary":{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/10.1002\/art.70374"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,20]]},"references-count":0,"alternative-id":["10.1002\/art.70374"],"URL":"https:\/\/doi.org\/10.1002\/art.70374","archive":["Portico"],"relation":{},"ISSN":["2326-5191","2326-5205"],"issn-type":[{"value":"2326-5191","type":"print"},{"value":"2326-5205","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,20]]},"assertion":[{"value":"2026-06-11","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-28","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-20","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"art.70374"}}