Semaphorin 3A in the Immune System: Twenty Years of Study

Abstract

Semaphorin 3A is a secreted glycoprotein, which was originally identifi ed as axon guidance factor in the neuronal system, but it also possesses immunoregulatory properties. Here, the eff ect of semaphorin 3A on T-lymphocytes, myeloid dendritic cells and macrophages is systematically analyzed on the bases of all publications available in the literature for 20 years. Expression of semaphorin 3A receptors -neuropilin-1 and plexins A -in these cells is described in details. The data obtained on human and murine cells is described comparatively. A comprehensive overview of the interaction of semaphorin 3A with mononuclear phagocyte system is presented for the fi rst time. Semaphorin 3A signaling mostly results in changes of the cytoskeletal machinery and cellular morphology that regulate pathways involved in migration, adhesion, and cell-cell cooperation of immune cells. Accumulating evidence indicates that this factor is crucially involved in various phases of immune responses, including initiation phase, antigen presentation, eff ector T cell function, infl ammation phase, macrophage activation, and polarization. In recent years, interest in this fi eld has increased signifi cantly because semaphorin 3A is associated with many human diseases and therefore can be used as a target for their treatment. Its involvement in the immune responses is important to study, because semaphorin 3A and its receptors turn to be a promising new therapeutic tools to be applied in many autoimmune, allergic, and oncology diseases.

Do Semaphorins Play a Role in Development of Fibrosis in Patients with Nonalcoholic Fatty Liver Disease?

“…It was reported that SEMA3A inhibits neutrophil migration, promotes a transition of classically activated (M1) macrophages toward a resolution phenotype and negatively regulates T-cell-mediated immune responses [ 22 , 23 , 24 ]. In patients with systemic lupus erythematosus reduced expression of SEMA3A correlated with inflammation and disease severity [ 25 ], and exogenous administration of SEMA3A was associated with markedly reduced articular inflammation in the rheumatoid arthritis mouse model [ 26 ].…”

Role of Semaphorin 3A in Kidney Development and Diseases

“…The basic domain is located at the C-terminus of SEMA3A. The C-terminus determines its affinity to neuropilin-1 (NRP1) (Figure 1) [3,38]. SEMA3A has two receptors: NRP1 is necessary for ligand binding, while plexin A is important to subsequent signal transduction.…”

“…NRP1 is a transmembrane protein with a molecular weight of 120-130 kDa. The extracellular part contains three kinds of domains, made up of two complement binding domains a1/a2, two coagulation factor V/VIII domains, and a c-domain, and is connected to the NRP1 cytoplasmic part (Figure 1) [3]. The signaling receptor Plexin A is a transmembrane glycoprotein with a SEMA3A-like extracellular part, which, implying their common evolutionary origin, is followed by three PSI domains and three IPT (Ig-like, plexins and transcription factors) domains.…”

“…SEMA3A also regulates immune systems, especially enhancing T-cell and B-cell regulatory properties [3]. Hence, it was reported that SEMA3A is involved in the pathogenesis of autoimmune diseases, including SLE [66], rheumatoid arthritis [96] and Sjogren's syndrome [97].…”

“…Class 1 and class 2 semaphorins have been identified in invertebrates, and class 3-7 semaphorins in vertebrates. In vertebrates, class 3 semaphorin (SEMA3A-3G) is the only member of secreted proteins [3]. In 1990, Raper et al isolated a molecule from embryonic chick brain that induced the collapse of neuronal growth cones in culture, and the molecule was originally named Collapsin [4,5], but it was renamed as SEMA3A.…”