Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0014070 (
encephalomyelitis
)
13,017
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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.
...
PMID:Defective sphingosine 1-phosphate receptor 1 (S1P1) phosphorylation exacerbates TH17-mediated autoimmune neuroinflammation. 2407 35
Fingolimod (FTY720, Gilenya), a sphingosine-1-phosphate receptor (S1PR) modulator, is one of the first-line immunomodulatory therapies for treatment of relapsing-remitting multiple sclerosis (MS). Human
S1PR1
variants have been reported to have functional heterogeneity in vitro, suggesting that S1PR1 function may influence FTY720 efficacy. In this study, we examined the influence of S1PR1 phosphorylation on response to FTY720 in neuroinflammation. We found that mice carrying a phosphorylation-defective
S1pr1
gene [S1PR1(
S5A
) mice] were refractory to FTY720 treatment in MOG
35-55
-immunized and Th17-mediated experimental autoimmune
encephalomyelitis
(EAE) models. Long-term treatment with FTY720 induced significant lymphopenia and suppressed Th17 response in the peripheral immune system via downregulating STAT3 phosphorylation in both WT and S1PR1(
S5A
) mice. However, FTY720 did not effectively prevent neuroinflammation in the S1PR1(
S5A
) EAE mice as a result of encephalitogenic cells expressing C-C chemokine receptor 6 (CCR6). Combined treatment with FTY720 and anti-CCR6 delayed disease progression in S1PR1(
S5A
) EAE mice, suggesting that CCR6-mediated cell trafficking can overcome the effects of FTY720. This work may have translational relevance regarding FTY720 efficacy in MS patients and suggests that cell type-specific therapies may enhance therapeutic efficacy in MS.
...
PMID:Effects of sphingosine-1-phosphate receptor 1 phosphorylation in response to FTY720 during neuroinflammation. 2769 72
The critical role of sphingosine-1-phosphate (S1P) signaling in lymphocyte trafficking is well recognized, however, the contribution of myeloid cell-S1P signaling in neuroimmunity is less well understood. We previously reported that C57BL/6J mice harboring phosphorylation defective S1P receptor 1 (S1P
1
) (with mutated serines in the carboxyl terminus, leading to impaired receptor internalization) [S1P
1
(
S5A
)] developed severe, T
H
17-dominant experimental autoimmune
encephalomyelitis
. In this study, we demonstrate that S1P
1
-mediated T
H
17 polarization is not an intrinsic T cell effect, but dependent on sustained S1P
1
signaling in myeloid cells. First, utilizing the S1P
1
(
S5A
) mice in the EAE model, we observed that S1P
1
activated and enhanced antigen presentation function in myeloid cells. Second, sequential phosphorylation of STAT3 occurred in dendritic cells, monocytes, and macrophages/microglia during neuroinflammation. Third, we show that pro-inflammatory (CD45
hi
CD11b
+
Ly6C
hi
) monocytes contribute to T
H
17 differentiation and neuroinflammation by regulating IL-6 expression. Finally, results from experiments utilizing myeloid cell-specific S1P
1
overexpression (S1pr1
f/stop/f
:LysM
Cre
) mice demonstrate that myeloid cell S1P
1
directly contributes to severity of neuroinflammation. These findings reveal the critical contribution of myeloid-S1P
1
signaling in CNS autoimmunity.
...
PMID:Myeloid sphingosine-1-phosphate receptor 1 is important for CNS autoimmunity and neuroinflammation. 3120 17
