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Induction of Inflammation and Fibrosis by Semaphorin 4A in Systemic Sclerosis
Author(s) -
Carvalheiro Tiago,
Affandi Alsya J.,
MalvarFernández Beatriz,
Dullemond Ilse,
Cossu Marta,
Ottria Andrea,
Mertens Jorre S.,
Giovan Barbara,
BonteMineur Femke,
Kok Marc R.,
Marut Wioleta,
Reedquist Kris A.,
Radstake Timothy R.,
García Samuel
Publication year - 2019
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.40915
Subject(s) - flow cytometry , inflammation , semaphorin , chemistry , fibroblast , fibrosis , microbiology and biotechnology , receptor , cytokine , blot , immunology , biology , medicine , in vitro , biochemistry , gene
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.