Semaphorin-3A (Sema-3A) is a secretory member of the semaphorin family that exerts regulatory functions at all phases of the immune response, both physiological and pathological. The main receptors transducing the Sema-3A signals comprise class A plexins (Plxns A1-A4) and neuropilin-1 (Nrp-1). The signaling pathways downstream of Sema-3A binding to its receptors are intimately associated with the pathogenesis of various immunological disorders, ranging from cancer to autoimmune diseases and allergies. The present review aims to provide an overview of the current knowledge on the role of Sema-3A in the pathogenesis of autoimmune rheumatic diseases (ARDs) and summarizes the recent findings concerning the expression status of Sema-3A, as well as its therapeutic value for the treatment of these disorders. Recent investigations have pointed out the involvement of Sema-3A in the pathogenesis of ARDs, systemic disorders that implicate the joints, bones, muscles, and connective tissues. Moreover, Sema-3A can diminish ARDs by suppressing the autoimmune reactions mediated by T- and B-cell hyperactivation. Noteworthy, Sema-3A functions to increase the regulatory features of T and B cells, thereby controlling ARDs. Yet, the overexpression of Sema-3A can also lead to the induction of ARDs. Besides, Sema-3A expression is dramatically reduced by microRNA (miR)-145-5p and miR-497-5p, demonstrating the inhibitory impact of these microRNAs on the Sema-3A expression. Altogether, these findings suggest the crucial roles of Sema-3A in ARDs pathogenesis and introduce it as a promising therapeutic tool for treating these diseases.
Keywords: Autoimmune diseases; Class A plexins; Nrp-1; Sema-3A; Treg cells.
© 2025. The Author(s), under exclusive licence to Springer Nature Switzerland AG.