Sphingosine-1-phosphate receptor modulator FTY720 attenuates experimental myeloperoxidase-ANCA vasculitis in a T cell-dependent manner
Sphingosine-1-phosphate receptor modulator FTY720 attenuates experimental myeloperoxidase-ANCA vasculitis in a T cell-dependent manner
复制标题
1-磷酸鞘氨醇受体调节剂 FTY720 以 T 细胞依赖性方式减轻实验性髓过氧化物酶-ANCA 血管炎
DOI：
10.1042/cs20200497
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发表时间：
2020
期刊：
影响因子：
6
通讯作者：
Ming-Hui Zhao
中科院分区：
文献类型：
--
作者：
Luo-Yi Wang;Xiao-Jing Sun;Chen Wang;Su-Fang Chen;Zhi-Ying Li;Min Chen;Mark A. Little;Ming-Hui Zhao
鞘氨醇-1-磷酸（S1 P）是一种多效溶鞘脂，来源于质膜脂质代谢。S1 P与其广泛表达的G蛋白偶联受体（S1 PR 1 -5）之间的相互作用在许多病理生理过程中至关重要。新出现的证据表明，S1 P受体在抗中性粒细胞胞浆抗体（ANCA）相关性血管炎（AAV）中的潜在作用。在本研究中，我们研究了三种不同的S1 P受体调节剂（FTY 720，SEW 2871和TY 52156）在公认的实验性自身免疫性血管炎（EAV）大鼠模型中的作用。治疗的效果进行了评估，临床病理参数，包括血尿，蛋白尿，新月体形成，肺出血，等。在体外功能研究进行了Jurkat T细胞系刺激血清髓过氧化物酶-AAV患者。我们发现，只有FTY 720治疗显着减轻血尿和蛋白尿，并减少肾小球新月体形成，肾小管间质病变和肺出血在EAV。FTY 720的减毒作用伴随肾脏T细胞浸润减少、肾脏S1 PR 1 mRNA表达上调和IL-1β表达下调，但不改变循环ANCA水平，表明FTY 720的治疗作用不依赖于B细胞。进一步的体外研究表明FTY 720孵育能显著抑制T细胞的增殖、粘附和迁移，并增加T细胞的凋亡。结论：S1 P调节剂FTY 720可通过减少和抑制T细胞来减轻EAV，有望成为治疗ANCA相关性血管炎的新方法。
Sphingosine-1-phosphate (S1P) is a pleiotropic lysosphingolipid derived from the metabolism of plasma membrane lipids. The interaction between S1P and its ubiquitously expressed G-protein-coupled receptors (S1PR1-5) is crucial in many pathophysiological processes. Emerging evidence suggested a potential role for S1P receptors in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). In the present study, we investigated the effects of three different S1P receptors modulators (FTY720, SEW2871 and TY52156) in a recognized rat model of experimental autoimmune vasculitis (EAV). The effects of treatments were evaluated with clinico-pathological parameters including hematuria, proteinuria, crescent formation, pulmonary hemorrhage, etc.In vitrofunctional studies were performed in a Jurkat T-cell line following stimulations of serum from myeloperoxidase-AAV patients. We found that only the FTY720 treatment significantly alleviated hematuria and proteinuria, and diminished glomerular crescent formation, renal tubulointerstitial lesions and pulmonary hemorrhage in EAV. The attenuation was accompanied by less renal T-cell infiltration, up-regulated mRNA of S1PR1 and down-regulated IL-1β in kidneys, but not altered circulating ANCA levels, suggesting that the therapeutic effects of FTY720 were B-cell independent. Furtherin vitrostudies demonstrated that FTY720 incubation could significantly inhibit the proliferation, adhesion, and migration, and increase apoptosis of T cells. In conclusion, the S1P modulator FTY720 could attenuate EAV through the reduction and inhibition of T cells, which might become a novel treatment of ANCA-associated vasculitis.