Defective sphingosine 1-phosphate receptor 1 (S1P1) phosphorylation exacerbates TH17-mediated autoimmune neuroinflammation.
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 phosphorylation enhances TH17 polarization and exacerbates autoimmune neuroinflammation. These mechanisms may be pathogenic in MS.
1] Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA. [2] Graduate Program in Immunology, Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts, USA. [3].
Christopher S
CS
Garris
Linfeng
L
Wu
Swati
S
Acharya
Ahmet
A
Arac
Victoria A
VA
Blaho
Yingxiang
Y
Huang
Byoung San
BS
Moon
Robert C
RC
Axtell
Peggy P
PP
Ho
Gary K
GK
Steinberg
David B
DB
Lewis
Raymond A
RA
Sobel
David K
DK
Han
Lawrence
L
Steinman
Michael P
MP
Snyder
Timothy
T
Hla
May H
MH
Han
D000818:Animals; D001344:Autopsy; D001921:Brain / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053612:Janus Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008246:Lysophospholipids / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells
D020381:Interleukin-17; D015850:Interleukin-6; D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C060506:sphingosine 1-phosphate; D053612:Janus Kinases; D013110:Sphingosine