Semaphorin 7A as a potential immune regulator and promising therapeutic target in rheumatoid arthritis

Jianmin Xie,Hao Wang

doi:10.1186/s13075-016-1217-5

Abstract

BackgroundSemaphorin 7A (Sema7A) is expressed by several different classes of lymphoid and myeloid cells and is a potent immunomodulator. We examined the role of Sema7A in modulating cellular immune responses and to provide experimental data validating the therapeutic potential of Sema7A in rheumatoid arthritis (RA).MethodsSoluble Sema7A (sSema7A) levels in the serum and synovial fluid from patients with RA or osteoarthritis, as well as cytokine secretions, were analyzed with an enzyme-linked immunosorbent assay. The cell surface levels and transcripts of Sema7A were evaluated in T cells and monocytes from patients with RA. The effect of Sema7A on the functions of primary T cells isolated from the peripheral blood of healthy donors was observed. Detection of the activation of the signal mediator focal adhesion kinase was performed by Western blotting. Shedding of sSema7A was evaluated in monocytes. The introduction of anti-Sema7A antibody to mice with collagen-induced arthritis (CIA) was observed in vivo.ResultsUpregulation of sSema7A levels in both the serum and synovial fluid of patients with RA was correlated with disease activity markers. sSema7A markedly increased Th1/Th17 cytokine secretion and induced evident upregulation of T-bet and retinoic acid receptor-related orphan nuclear receptor γt levels in T cells. Cell surface Sema7A was cleaved by a disintegrin and metalloprotease 17 (ADAM17) in monocytes. Interleukin-6 and tumor necrosis factor-α stimulated ADAM17 secretion in synovial macrophages. Blocking of β1-integrin abrogated the Sema7A-mediated cytokine secretion. Treatment with an anti-Sema7A antibody significantly attenuated CIA.ConclusionsThese findings indicate that Sema7A as a potent activator of T cells and monocytes in the immune response contributes to the inflammation and progression of RA, suggesting its therapeutic potential in the treatment of RA.

Highlights

Semaphorin 7A (Sema7A) is expressed by several different classes of lymphoid and myeloid cells and is a potent immunomodulator
The anti-Sema7A antibody suppressed IL-6 and tumor necrosis factor-α (TNF-α) secretion stimulated by Soluble Sema7A (sSema7A) (Fig. 2e). These results showed that sSema7A can induce inflammatory cytokine production by monocytes/macrophages, suggesting that Sema7A might have a pathogenic role in rheumatoid arthritis (RA)
The results validated the detection of sSema7A in the shedding analysis and suggest that a disintegrin and metalloprotease 17 (ADAM17) is probably the shedddase. Consistent with this finding, we measured the enhanced levels of ADAM17 in the serum and synovial fluid of patients with RA (Fig. 5b and c), and we found that TNF-α and IL-6 stimulated the secretion of ADAM17 by monocytes/macrophages detected in the patients with RA in this study (Fig. 5d)

Summary

Introduction

Semaphorin 7A (Sema7A) is expressed by several different classes of lymphoid and myeloid cells and is a potent immunomodulator. Rheumatoid arthritis (RA) is an autoimmune and systemic inflammatory disorder characterized by synovial inflammation, destruction of cartilage and bone, and systemic manifestations [1, 2]. RA synovial inflammation evokes arthritis symptoms and causes articular bone and cartilage destruction. Xie and Wang Arthritis Research & Therapy (2017) 19:10. They are divided into eight classes based on sequence similarities and distinct structural features [7, 8]. Semaphorins were initially described for their role in axon guidance during neurogenesis [9]. Semaphorins are involved in physiological processes such as organogenesis, immune cell regulation, and vascular growth [10]

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