Defective sphingosine 1-phosphate receptor 1 (S1P1) phosphorylation exacerbates TH17-mediated autoimmune neuroinflammation.
Defective sphingosine 1-phosphate receptor 1 (S1P1) phosphorylation exacerbates TH17-mediated autoimmune neuroinflammation.
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鞘氨醇-1-磷酸(S1P)信号调节淋巴细胞从淋巴器官进入全身循环。鞘氨醇磷酸受体1(S1P1)激动剂FTY-720(Gilenya™)阻止免疫贩运并防止多发性硬化症(MS)复发。然而，已经报道了S1P-S1P1信号的替代机制。多发性硬化症脑损伤的磷酸蛋白质组学分析显示，S1P1在S351上发生磷酸化，这是受体内化的关键残基。携带编码磷酸化缺陷受体[S1P1(S5A)]的S1PR1基因的突变小鼠由于辅助性T细胞(TH)17介导的外周免疫和神经系统的自身免疫而发生严重的实验性自身免疫性脑脊髓炎(EAE)。S1P1通过白细胞介素6(IL-6)直接激活Janus样激酶信号转导和转录激活因子3(JAK-STAT3)通路。受损的S1P1磷酸化增强TH17极化并加剧自身免疫性神经炎症。这些机制可能是MS的致病机制。
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.