Semaphorin 4D Contributes to Rheumatoid Arthritis by Inducing Inflammatory Cytokine Production: Pathogenic and Therapeutic Implications

Abstract

ObjectiveSemaphorin 4D (Sema4D)/CD100 has pleiotropic roles in immune activation, angiogenesis, bone metabolism, and neural development. We undertook this study to investigate the role of Sema4D in rheumatoid arthritis (RA).MethodsSoluble Sema4D (sSema4D) levels in serum and synovial fluid were analyzed by enzyme‐linked immunosorbent assay. Cell surface expression and transcripts of Sema4D were analyzed in peripheral blood cells from RA patients, and immunohistochemical staining of Sema4D was performed in RA synovium. Generation of sSema4D was evaluated in an ADAMTS‐4–treated monocytic cell line (THP‐1 cells). The efficacy of anti‐Sema4D antibody was evaluated in mice with collagen‐induced arthritis (CIA).ResultsLevels of sSema4D were elevated in both serum and synovial fluid from RA patients, and disease activity markers were correlated with serum sSema4D levels. Sema4D‐expressing cells also accumulated in RA synovium. Cell surface levels of Sema4D on CD3+ and CD14+ cells from RA patients were reduced, although levels of Sema4D transcripts were unchanged. In addition, ADAMTS‐4 cleaved cell surface Sema4D to generate sSema4D in THP‐1 cells. Soluble Sema4D induced tumor necrosis factor α (TNFα) and interleukin‐6 (IL‐6) production from CD14+ monocytes. IL‐6 and TNFα induced ADAMTS‐4 expression in synovial cells. Treatment with an anti‐Sema4D antibody suppressed arthritis and reduced proinflammatory cytokine production in CIA.ConclusionA positive feedback loop involving sSema4D/IL‐6 and TNFα/ADAMTS‐4 may contribute to the pathogenesis of RA. The inhibition of arthritis by anti‐Sema4D antibody suggests that Sema4D represents a potential therapeutic target for RA.

Netrin‐1 and its receptor Unc5b are novel targets for the treatment of inflammatory arthritis

“…On one hand, high levels of semaphoring (Sema) 4D have been directly associated with RA. Thus, serum levels of Sema4D correlate with known clinical and biologic markers of RA, which suggests that Sema4D is a potentially useful biomarker for RA disease activity (36). On the other hand, protein expression of Sema3A in synovial lining cells was decreased in RA tissues, with a negative correlation between disease activity score in patients with RA and Sema3A expression (37).…”

Adenosine A 2A receptor (A2AR) stimulation modulates expression of semaphorins 4D and 3A, regulators of bone homeostasis

“…Sema3A, originally identified as a diffusible axonal chemorepellent that modulates axon guidance and growth (19), is produced by osteoblasts and binds to PlexinA1/ Neuropilin-1 to inhibit both RANKL-induced osteoclast differentiation by inhibition of immunoreceptor tyrosinebased activation motif and RhoA signaling (14,20) and to stimulate osteoblast differentiation and function (12,(20)(21)(22). By binding to Neuropilin-1, Sema3A activates canonical Wnt/b-catenin signaling on mesenchymal precursors to stimulate osteoblast differentiation and inhibit adipocyte formation (14).…”

Semaphorin 4C: A Novel Component of B-Cell Polarization in Th2-Driven Immune Responses

“…Interaction of Sema4D-expressing CD5 + B-cells or leukemic-B-cells with Plexin-B1-expressing cells led to improved tumor survival. Sema4D is also involved in interaction between T cells and B-cells (39, 40), and in mediating endothelial cell migration (41), while Sema4A is known to activate regulatory T-lymphocytes and cytotoxic T cells (42–44). Interestingly, Sema4A and 4D utilize specific plexins as their primary non-hematopoietic receptors, but appear to interact with different binding partners in the immune system.…”