{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T13:28:50Z","timestamp":1790947730971,"version":"4.1.0"},"reference-count":50,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2019,8,27]],"date-time":"2019-08-27T00:00:00Z","timestamp":1566864000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis & Rheumatology"],"published-print":{"date-parts":[[2019,10]]},"abstract":"\n Objective<\/jats:title>\n \n To analyze the potential role of semaphorin 4A (Sema4A) in inflammatory and fibrotic processes involved in the pathology of systemic sclerosis (\n SS<\/jats:styled-content>\n c).\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Sema4A levels in the plasma of healthy controls (n = 11) and\n SS<\/jats:styled-content>\n c patients (n = 20) were determined by enzyme\u2010linked immunosorbent assay (\n ELISA<\/jats:styled-content>\n ). The expression of Sema4A and its receptors in monocytes and\n CD<\/jats:styled-content>\n 4+ T cells from healthy controls and\n SS<\/jats:styled-content>\n c patients (n = 6\u20137 per group) was determined by\n ELISA<\/jats:styled-content>\n and flow cytometry. Th17 cytokine production by\n CD<\/jats:styled-content>\n 4+ T cells (n = 5\u20137) was analyzed by\n ELISA<\/jats:styled-content>\n and flow cytometry. The production of inflammatory mediators and extracellular matrix (\n ECM<\/jats:styled-content>\n ) components by dermal fibroblast cells (n = 6) was analyzed by quantitative polymerase chain reaction,\n ELISA<\/jats:styled-content>\n , Western blotting, confocal microscopy, and\n ECM<\/jats:styled-content>\n deposition assay.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Plasma levels of Sema4A, and Sema4A expression by circulating monocytes and\n CD<\/jats:styled-content>\n 4+ T cells, were significantly higher in\n SS<\/jats:styled-content>\n c patients than in healthy controls (\n P<\/jats:italic>\n < 0.05). Inflammatory mediators significantly up\u2010regulated the secretion of Sema4A by monocytes and\n CD<\/jats:styled-content>\n 4+ T cells from\n SS<\/jats:styled-content>\n c patients (\n P<\/jats:italic>\n < 0.05 versus unstimulated\n SS<\/jats:styled-content>\n c cells). Functional assays showed that Sema4A significantly enhanced the expression of Th17 cytokines induced by\n CD<\/jats:styled-content>\n 3\/\n CD<\/jats:styled-content>\n 28 in total\n CD<\/jats:styled-content>\n 4+ T cells as well in different\n CD<\/jats:styled-content>\n 4+ T cell subsets (\n P<\/jats:italic>\n < 0.05 versus unstimulated\n SS<\/jats:styled-content>\n c cells). Finally, Sema4A induced a profibrotic phenotype in dermal fibroblasts from both healthy controls and\n SS<\/jats:styled-content>\n c patients, which was abrogated by blocking or silencing the expression of Sema4A receptors.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n Our findings indicate that Sema4A plays direct and dual roles in promoting inflammation and fibrosis, 2 main features of\n SS<\/jats:styled-content>\n c, suggesting that Sema4A might be a novel therapeutic target in\n SS<\/jats:styled-content>\n c.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/art.40915","type":"journal-article","created":{"date-parts":[[2019,4,23]],"date-time":"2019-04-23T07:11:29Z","timestamp":1556003489000},"page":"1711-1722","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Induction of Inflammation and Fibrosis by Semaphorin 4A in Systemic Sclerosis"],"prefix":"10.1002","volume":"71","author":[{"given":"Tiago","family":"Carvalheiro","sequence":"first","affiliation":[{"name":"University Medical Center Utrecht University of Utrecht Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alsya J.","family":"Affandi","sequence":"additional","affiliation":[{"name":"University Medical Center Utrecht University of Utrecht Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz","family":"Malvar\u2010Fern\u00e1ndez","sequence":"additional","affiliation":[{"name":"University Medical Center Utrecht University of Utrecht Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilse","family":"Dullemond","sequence":"additional","affiliation":[{"name":"University Medical Center Utrecht University of Utrecht Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Cossu","sequence":"additional","affiliation":[{"name":"University Medical Center Utrecht University of Utrecht Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Ottria","sequence":"additional","affiliation":[{"name":"University Medical Center Utrecht University of Utrecht Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorre S.","family":"Mertens","sequence":"additional","affiliation":[{"name":"University Medical Center Utrecht University of Utrecht Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Giovannone","sequence":"additional","affiliation":[{"name":"University Medical Center Utrecht University of Utrecht Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Femke","family":"Bonte\u2010Mineur","sequence":"additional","affiliation":[{"name":"Maasstad Hospital Rotterdam Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc R.","family":"Kok","sequence":"additional","affiliation":[{"name":"Maasstad Hospital Rotterdam Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wioleta","family":"Marut","sequence":"additional","affiliation":[{"name":"University Medical Center Utrecht University of Utrecht Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kris A.","family":"Reedquist","sequence":"additional","affiliation":[{"name":"University Medical Center Utrecht University of Utrecht Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy 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