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

Tiago Carvalheiro, Alsya J Affandi, Beatriz Malvar-Fernández, Ilse Dullemond, Marta Cossu, Andrea Ottria, Jorre S Mertens, Barbara Giovannone, Femke Bonte-Mineur, Marc R Kok, Wioleta Marut, Kris A Reedquist, Timothy R Radstake, Samuel García

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)


OBJECTIVE: To analyze the potential role of semaphorin 4A (Sema4A) in inflammatory and fibrotic processes involved in the pathology of systemic sclerosis (SSc).

METHODS: Sema4A levels in the plasma of healthy controls (n = 11) and SSc patients (n = 20) were determined by enzyme-linked immunosorbent assay (ELISA). The expression of Sema4A and its receptors in monocytes and CD4+ T cells from healthy controls and SSc patients (n = 6-7 per group) was determined by ELISA and flow cytometry. Th17 cytokine production by CD4+ 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 CD4+ T cells, were significantly higher in SSc patients than in healthy controls (P < 0.05). Inflammatory mediators significantly up-regulated the secretion of Sema4A by monocytes and CD4+ T cells from SSc patients (P < 0.05 versus unstimulated SSc cells). Functional assays showed that Sema4A significantly enhanced the expression of Th17 cytokines induced by CD3/CD28 in total CD4+ T cells as well in different CD4+ T cell subsets (P < 0.05 versus unstimulated SSc cells). Finally, Sema4A induced a profibrotic phenotype in dermal fibroblasts from both healthy controls and SSc 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 SSc, suggesting that Sema4A might be a novel therapeutic target in SSc.

Original languageEnglish
Pages (from-to)1711-1722
Number of pages12
JournalArthritis & rheumatology (Hoboken, N.J.)
Issue number10
Publication statusPublished - Oct 2019
Externally publishedYes


  • Adult
  • Blotting, Western
  • CD4-Positive T-Lymphocytes/immunology
  • Case-Control Studies
  • Cytokines/immunology
  • Enzyme-Linked Immunosorbent Assay
  • Extracellular Matrix/metabolism
  • Female
  • Fibroblasts/immunology
  • Fibrosis/metabolism
  • Humans
  • Inflammation/immunology
  • Male
  • Microscopy, Confocal
  • Middle Aged
  • Monocytes/immunology
  • Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Scleroderma, Systemic/immunology
  • Semaphorins/metabolism
  • Skin/cytology
  • Th17 Cells/immunology


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