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Objective  To analyze the potential role of semaphorin 4A (Sema4A) in inflammatory and fibrotic processes involved in the pathology of systemic sclerosis ( SS c).    Methods  Sema4A levels in the plasma of healthy controls (n = 11) and  SS c patients (n = 20) were determined by enzyme‐linked immunosorbent assay ( ELISA ). The expression of Sema4A and its receptors in monocytes and  CD 4+ T cells from healthy controls and  SS c patients (n = 6–7 per group) was determined by  ELISA  and flow cytometry. Th17 cytokine production by  CD 4+ T cells (n = 5–7) was analyzed by  ELISA  and flow cytometry. The production of inflammatory mediators and extracellular matrix ( ECM ) components by dermal fibroblast cells (n = 6) was analyzed by quantitative polymerase chain reaction,  ELISA , Western blotting, confocal microscopy, and  ECM  deposition assay.    Results  Plasma levels of Sema4A, and Sema4A expression by circulating monocytes and  CD 4+ T cells, were significantly higher in  SS c patients than in healthy controls ( P  < 0.05). Inflammatory mediators significantly up‐regulated the secretion of Sema4A by monocytes and  CD 4+ T cells from  SS c patients ( P  < 0.05 versus unstimulated  SS c cells). Functional assays showed that Sema4A significantly enhanced the expression of Th17 cytokines induced by  CD 3/ CD 28 in total  CD 4+ T cells as well in different  CD 4+ T cell subsets ( P  < 0.05 versus unstimulated  SS c cells). Finally, Sema4A induced a profibrotic phenotype in dermal fibroblasts from both healthy controls and  SS c patients, which was abrogated by blocking or silencing the expression of Sema4A receptors.    Conclusion  Our findings indicate that Sema4A plays direct and dual roles in promoting inflammation and fibrosis, 2 main features of  SS c, suggesting that Sema4A might be a novel therapeutic target in  SS c.

Induction of Inflammation and Fibrosis by Semaphorin 4A in Systemic Sclerosis