The role of immune semaphorins in the pathogenesis of multiple sclerosis: Potential therapeutic targets

The immune and nervous systems possess a highly intricate network of synaptic connections, shared messenger molecules, and exquisite communication ways, allowing intercellular signal transduction. The semaphorins (Semas) were initially identified as axonal guidance molecules in the development of the nervous system but later were found to be implicated also in regulating the immune system, known in this case as the "immune Semas" or "immunoregulatory Semas". Increasingly, these molecules are involved in multiple aspects of both physiological and pathological immune responses and were recently indicated to take part in various immunological disorders, encompassing allergy, cancer, and autoimmunity. Semas transduce signals by connecting to their cognate receptors, namely, plexins and neuropilins. Some of them, like Sema-3F, have been found to function as the inducer of the remyelination process whereas some others, like Sema-3A and Sema-4D, act to inhibit this process, either directly or indirectly. Besides, Sema-4A is crucial to the differentiation of T helper type 1 (Th1) and Th17 cells that are potentially involved in the pathogenesis of multiple sclerosis (MS), an autoimmune disease of the central nervous system. This review aims to reveal the role of immune Semas in the pathogenesis of MS and its animal model, experimental autoimmune encephalomyelitis, focusing on the therapeutic usages of these molecules to treat this neurodegenerative disease.