Truncated-semaphorin3A is a potential regulatory molecule to restore immune homeostasis in immune-mediated diseases

Abstract

Regulatory molecules have recently been recognized for their beneficial effects in the treatment of immune-mediated diseases, rather than using cytotoxic immune-suppressing drugs, which are associated with many unwanted side effects. Semaphorin3A (sema3A), a unique regulatory master of the immune system, was shown to be decreased in the serum of systemic lupus erythematosus (SLE) patients, in association with disease severity. Later, we were able to show its extremely beneficial effect in treating lupus nephritis in the NZB/W mice model. The mechanisms by which sema3A maintains its regulatory effect is by binding the regulatory receptor CD72 on B cells, thereby reducing the threshold of BCR signaling on B cells and reducing the production of pro-inflammatory cytokines. The aim of this study was to generate a stable sema3A molecule, easy to produce with a higher binding capacity to CD72 receptor rather than to Neuropilin-1 (NRP-1) receptor, which is expressed in many cell types. Using the crystallographic structure of parental sema3A, we synthesized a new secreted (shorter) sema3A derivative, which we called truncated sema3A (T-sema3A). The new molecule lacked the NRP-1 binding domain (the C-terminal site) and has an artificial dimerization site at position 257 (serine residue was exchanged with a cysteine residue). To facilitate the purification of this molecule we added Histidine epitope tag in frame upstream to a stop codon. This construct was transfected using a viral vector to 293HEK cells to generate cells stably expressing T-sema3A. T-sema3A is shown to be with a higher binding ability to CD72 than to NRP-1 as demonstrated by a homemade ELISA. In addition, T-sema3A was shown to be a regulatory agent which can induce the expression of IL-10 and TGF-β and reduce the secretion of pro-inflammatory cytokines such as IL-6, IFN-γ, and IL-17A from human T and B-lymphocytes. Keeping this in mind, T-sema3A is highly effective in maintaining immune homeostasis, therefore, becoming a potential agent in restoring the regulatory status of the immune system in immune-mediated diseases.

Construction of an IFNAR1 knockout MDBK cell line using CRISPR/Cas9 and its effect on bovine virus replication

“…Conversely, the significant downregulation of MGAT2 may reduce the n-acetylglucosamine modification on the cell surface, thereby affecting the interaction between the virus and host cells, and inhibiting virus replication ( Figure 4F ) ( 29 ). Although the specific roles of some DEGs in antiviral defense are unclear, the upregulation and downregulation of immune system-related DEGs, including SEMA3A ( 30 ), PADI1 ( 31 ), and MAP2K6 ( 32 ), as well as cell survival-related DEGs like STC1 ( 33 ), HSPA6 ( 34 ), and FGF17 ( 35 ), reflect the complex adaptability of BVDV-infected IFNAR1 knockout cells in antiviral defense. Further research will contribute to a deeper understanding of the specific roles and mechanisms of these genes in antiviral defense.…”

The role of Semaphorin 3A in oral diseases

“…The role of SEMA3A in oral diseases, especially in periodontitis and AP, has been studied to some extent. An experimental study on SEMA3A‐related immunosuppressants has also been conducted (Eiza et al, 2022). These findings provide compelling evidence that SEMA3A holds significant potential as a crucial target for treating oral diseases.…”

The Role of Semaphorins in the Pathogenesis of Rheumatoid Arthritis

“…It can be transfected using a viral vector. Its function in preserving immune homeostasis makes it a potential therapeutic agent [52].…”

“…It can be transfected using a viral vector. Its function in preserving immune homeostasis makes it a potential therapeutic agent [52]. Class 3 semaphorins participate in FLS-mediated joint destruction and regulate the invasive activity of FLSs.…”