Monday, 14 October 2013

Sphinogosine-1-Phosphate receptor activation and CNS disease

Garris CS, Wu L, Acharya S, Arac A, Blaho VA, Huang Y, Moon BS, Axtell RC, Ho PP, Steinberg GK, Lewis DB, Sobel RA, Han DK, Steinman L, Snyder MP, Hla T, Han MH. Defective sphingosine 1-phosphate receptor 1 (S1P1) phosphorylation exacerbates TH17-mediated autoimmune neuroinflammation.Nat Immunol. 2013 Sep  doi: 10.1038/ni.2730. [Epub ahead of print]


Sphingosine 1-phosphate (S1P) signaling regulates lymphocyte egress from lymphoid organs into systemic circulation. The sphingosine phosphate receptor 1 (S1P1) agonist FTY-720 (Gilenya) arrests immune trafficking and prevents multiple sclerosis (MS) relapses. However, alternative mechanisms of S1P-S1P1 signaling have been reported. Phosphoproteomic analysis of MS brain lesions revealed S1P1 phosphorylation on S351, a residue crucial for receptor internalization. Mutant mice harboring an S1pr1 gene encoding phosphorylation-deficient receptors (S1P1(S5A)) developed severe experimental autoimmune encephalomyelitis (EAE) due to autoimmunity mediated by interleukin 17 (IL-17)-producing helper T cells (TH17 cells) in the peripheral immune and nervous system. S1P1 directly activated the Jak-STAT3 signal-transduction pathway via IL-6. Impaired S1P1  In this study phosphorylation enhances TH17 polarization and exacerbates autoimmune neuroinflammation. These mechanisms may be pathogenic in MS.
S1P1 receptor is one of the receptors on which Gilenya works when receptors are activated often they become phosphorylated with means a phosphate group binds to serine (Amino acid) in a protein to often activate it. When S1P1 is activated the receptor is down regulated and this is what Gilenya does. In this study when a deficit in the phosphorylation of S1P1 occurs it can may EAE worse. However in MS lesions phosphorylation is occurring and can result in down regulation of S1P1. However, we are not sure what the significance is. Down regulation of S1P!in lymph glands is the mechanism on which Gilenya acts. Gilenya can accumulate in brain but it is not totally clear what it does there. Does it work on S1P1 on brain cells or S1P5? 

It is very clear from ECTRIMS that the blood is in the water and the Pharma Sharks are circling in on this target. There a large number of variants of S1P1 receptor blockers in development ready to push in to the Gilenya space.

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