Defective sphingosine 1-phosphate receptor 1 (S1P1) phosphorylation exacerbates TH17-mediated autoimmune neuroinflammation

Abstract

Sphingosine-1-phosphate (S1P) signaling regulates lymphocyte egress from lymphoid organs into systemic circulation. 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 a S1pr1 gene encoding phosphorylation-deficient receptors [S1P1(S5A)] developed severe experimental autoimmune encephalomyelitis (EAE) due to T helper (TH) 17-mediated autoimmunity in the peripheral immune and nervous system. S1P1 directly activated Janus-like kinase–signal transducer and activator of transcription 3 (JAK-STAT3) pathway via interleukin 6 (IL-6). Impaired S1P1 phosphorylation enhances TH17 polarization and exacerbates autoimmune neuroinflammation. These mechanisms may be pathogenic in MS.

An update on the biology of sphingosine 1-phosphate receptors

“…However, T cell S1P 1 may also regulate the activation and differentiation status of these immune cells. Deletion of T cell S1P 1 signifi cantly suppresses the ability of these cells to be polarized to T-helper (Th)17 in vitro ( 72 ). Conversely, when EAE was induced in mice expressing an internalizationdefective S1P 1 (S5A), this signifi cantly increased polarization of T cells to the Th17 phenotype resulting in increased disease pathology and immune cell infi ltration into the CNS ( 72 ).…”

“…Deletion of T cell S1P 1 signifi cantly suppresses the ability of these cells to be polarized to T-helper (Th)17 in vitro ( 72 ). Conversely, when EAE was induced in mice expressing an internalizationdefective S1P 1 (S5A), this signifi cantly increased polarization of T cells to the Th17 phenotype resulting in increased disease pathology and immune cell infi ltration into the CNS ( 72 ). S1P 1 is also expressed on CD4 T cells isolated from human rheumatoid arthritis patients ( 73 ).…”

Individual variation of human S1P1 coding sequence leads to heterogeneity in receptor function and drug interactions

“…I45T and G305C mutants phenocopy a S1P 1 (S5A) mutant in which fi ve serine residues in the carboxyl-terminal region are substituted with alanine. Recently, our group reported that S1P 1 (S5A) mutant mice showed enhanced autoimmunity and developed severe experimental autoimmune encephalomyelitis ( 26 ). Thus, impairment of the receptor internalization in I45T and G305C mutants may result in increased autoimmunity as observed in S1P 1 (S5A) mice, raising a possibility that these SNPs can be potential risk factors for autoimmune diseases.…”

“…FTY720 inhibits the egress of lymphocytes from secondary lymphoid organs by inducing internalization and irreversible S1P 1 degradation in the proteasome ( 25,30 ). Recently, our group showed that mutant mice harboring the S1PR1 gene encoding phosphorylation-defi cient, and as such endocytosis-defi cient, receptors [S1P 1 (S5A)] developed severe experimental autoimmune encephalomyelitis due to T helper 17 cell-mediated autoimmunity, both in the peripheral immune system and the nervous system ( 26 ). This S1P 1 (S5A) receptor shows resistance to FTY720-induced degradation both in vivo and in vitro ( 25,30 ).…”

“…This endocytosis/ recycling pathway is essential for the regulation of S1P 1 activity. Impairment of the receptor endocytosis results in enhanced signaling and hyper-immune consequences, whereas vascular endothelial function is enhanced (24)(25)(26).…”