Modulation of Specific Sphingosine-1-Phosphate Receptors Augments a Repair Mediating Schwann Cell Phenotype

Abstract

Transdifferentiation of Schwann cells is essential for functional peripheral nerve regeneration after injury. By activating a repair program, Schwann cells promote functional axonal regeneration and remyelination. However, chronic denervation, aging, metabolic diseases, or chronic inflammatory processes reduce the transdifferentiation capacity and thus diminish peripheral nerve repair. It was recently described that the sphingosine-1-phosphate receptor (S1PR) agonist Fingolimod enhances the Schwann cell repair phenotype by activation of dedifferentiation markers and concomitant release of trophic factors resulting in enhanced neurite growth. Since Fingolimod targets four out of five S1PRs (S1P1, S1P3-5) possibly leading to non-specific adverse effects, identification of the main receptor(s) responsible for the observed phenotypic changes is mandatory for future specific treatment approaches. Our experiments revealed that S1P3 dominates and that along with S1P1 acts as the responsible receptor for Schwann cell transdifferentiation as revealed by the combinatory application of specific agonists and antagonists. Targeting both receptors reduced the expression of myelin-associated genes, increased PDGF-BB representing enhanced trophic factor expression likely to result from c-Jun induction. Furthermore, we demonstrated that S1P4 and S1P5 play only a minor role in the adaptation of the repair phenotype. In conclusion, modulation of S1P1 and S1P3 could be effective to enhance the Schwann cell repair phenotype and thus stimulate proper nerve repair.

Identification of gene signatures and molecular mechanisms underlying the mutual exclusion between psoriasis and leprosy

“…In the context of leprosy, the bacterium can infect Schwann cells, resulting in damage to peripheral nerves 65 . Schwann cells are acknowledged for their sphingolipid production 66 , and their infection may disrupt the delicate balance of sphingolipids in nerve cells, potentially contributing to nerve damage. In addition, Mycobacterium leprae has been demonstrated to exert influence on host immune responses by altering the host's sphingolipid metabolism 67 , thereby impacting the immune system's efficacy in combating the infection.…”

Differences in the ultrastructure of neurons in the spinal ganglion and dorsal rootlet between rats treated with cisplatin only versus co‐administration with a sphingosine 1‐phosphate receptor 2 agonist in attenuating neuropathy and allodynia

“…21 The S1P3 receptor helps to restore gap-junctional communication between neurons and astrocytes, while the S1P1 and S1P5 receptors help to restore communication with oligodendrocytes. 21 S1P receptor is essential to protect sensory nerve and neuroepithelial cells of the cochlea and to mitigate neuropathy and allodynia in cisplatin-induced neuropathy in rat models. 10 Another S1P receptor subtype, the S1P2 receptor, is coupled to distinct G protein α subtypes, including G12/13, Gq, and Gi.…”

“…These are responsible for inflammatory responses 18–20 . They also activate a repair program to promote axonal regeneration and the remyelination activity of SCs 21 . Fingolimod, which is a sphingosine‐1‐phosphate receptor (S1P1 and S1P3‐5) agonist, promotes SC function in terms of remyelination activity and promotes regeneration of axons, through action at S1P 1 and S1P 3 by receptors 21 .…”

“…They also activate a repair program to promote axonal regeneration and the remyelination activity of SCs 21 . Fingolimod, which is a sphingosine‐1‐phosphate receptor (S1P1 and S1P3‐5) agonist, promotes SC function in terms of remyelination activity and promotes regeneration of axons, through action at S1P 1 and S1P 3 by receptors 21 . The S1P3 receptor helps to restore gap‐junctional communication between neurons and astrocytes, while the S1P1 and S1P5 receptors help to restore communication with oligodendrocytes 21 .…”

“…Fingolimod, which is a sphingosine‐1‐phosphate receptor (S1P1 and S1P3‐5) agonist, promotes SC function in terms of remyelination activity and promotes regeneration of axons, through action at S1P 1 and S1P 3 by receptors 21 . The S1P3 receptor helps to restore gap‐junctional communication between neurons and astrocytes, while the S1P1 and S1P5 receptors help to restore communication with oligodendrocytes 21 . S1P receptor is essential to protect sensory nerve and neuroepithelial cells of the cochlea and to mitigate neuropathy and allodynia in cisplatin‐induced neuropathy in rat models 10 …”