Renal Division, Department of Medicine, Peking University First Hospital; Peking University Institute of Nephrology, Beijing, China.
Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.
Rheumatology (Oxford). 2024 Sep 1;63(9):2578-2589. doi: 10.1093/rheumatology/keae320.
Increasing studies demonstrated the importance of C5a and anti-neutrophil cytoplasmic antibody (ANCA)-induced neutrophil activation in the pathogenesis of ANCA-associated vasculitis (AAV). Sphingosine-1-phosphate (S1P) acts as a downstream effector molecule of C5a and enhances neutrophil activation induced by C5a and ANCA. The current study investigated the role of a S1P receptor modulator, FTY720, in experimental autoimmune vasculitis (EAV) and explored the immunometabolism-related mechanisms of FTY720 in modulating ANCA-induced neutrophil activation.
The effects of FTY720 in EAV were evaluated by quantifying haematuria, proteinuria, crescent formation, tubulointerstitial injury and pulmonary haemorrhage. RNA sequencing of renal cortex and gene enrichment analysis were performed. The proteins of key identified pathways were analysed in neutrophils isolated from peripheral blood of patients with active AAV and normal controls. We assessed the effects of FTY720 on ANCA-induced neutrophil respiratory burst and neutrophil extracellular traps formation (NETosis).
FTY720 treatment significantly attenuated renal injury and pulmonary haemorrhage in EAV. RNA sequencing analyses of renal cortex demonstrated enhanced fatty acid oxidation (FAO) and peroxisome proliferator-activated receptor (PPAR) signalling in FTY720-treated rats. Compared with normal controls, patients with active AAV showed decreased FAO in neutrophils. FTY720-treated differentiated HL-60 cells showed increased expression of carnitine palmitoyltransferase 1a (CPT1a) and PPARα. Blocking or knockdown of CPT1a or PPARα in isolated human neutrophils and HL-60 cells reversed the inhibitory effects of FTY720 on ANCA-induced neutrophil respiratory burst and NETosis.
FTY720 attenuated renal injury in EAV through upregulating FAO via the PPARα-CPT1a pathway in neutrophils, offering potential immunometabolic targets in AAV treatment.
越来越多的研究表明 C5a 和抗中性粒细胞胞质抗体（ANCA）诱导的中性粒细胞活化在 ANCA 相关性血管炎（AAV）发病机制中的重要性。1-磷酸鞘氨醇（S1P）作为 C5a 的下游效应分子，增强 C5a 和 ANCA 诱导的中性粒细胞活化。本研究探讨了 S1P 受体调节剂 FTY720 在实验性自身免疫性血管炎（EAV）中的作用，并探讨了 FTY720 调节 ANCA 诱导的中性粒细胞活化的免疫代谢相关机制。
通过定量血尿、蛋白尿、新月体形成、肾小管间质损伤和肺出血来评估 FTY720 在 EAV 中的作用。对肾皮质进行 RNA 测序和基因富集分析。分析来自活动期 AAV 患者和正常对照者外周血分离的中性粒细胞中关键鉴定途径的蛋白质。我们评估了 FTY720 对 ANCA 诱导的中性粒细胞呼吸爆发和中性粒细胞胞外陷阱形成（NETosis）的影响。
FTY720 治疗显著减轻 EAV 中的肾损伤和肺出血。肾皮质 RNA 测序分析表明，FTY720 治疗的大鼠中脂肪酸氧化（FAO）和过氧化物酶体增殖物激活受体（PPAR）信号增强。与正常对照组相比，活动期 AAV 患者的中性粒细胞中 FAO 减少。FTY720 处理的分化 HL-60 细胞中肉碱棕榈酰转移酶 1a（CPT1a）和 PPARα的表达增加。在分离的人中性粒细胞和 HL-60 细胞中阻断或敲低 CPT1a 或 PPARα，逆转了 FTY720 对 ANCA 诱导的中性粒细胞呼吸爆发和 NETosis 的抑制作用。
FTY720 通过在中性粒细胞中上调 FAO 来减轻 EAV 中的肾损伤，通过 PPARα-CPT1a 途径为 AAV 治疗提供潜在的免疫代谢靶点。
