FTY720 ameliorates experimental MPO-ANCA-associated vasculitis by regulating fatty acid oxidation via the neutrophil PPARα-CPT1a pathway.

Autor:	Wang RX; 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.; Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China., Wang LY; 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.; Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China., Han XY; 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.; Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China., Chen SF; 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.; Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China., Sun XJ; 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.; Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China., Li ZY; 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.; Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China., Little MA; Trinity Kidney Centre, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland.; Irish Centre for Vascular Biology, Trinity College Dublin, Dublin, Ireland., Zhao MH; 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.; Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China.; Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China.; Peking-Tsinghua Center for Life Sciences, Beijing, China., Chen M; 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.; Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China.; Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China.
Jazyk:	angličtina
Zdroj:	Rheumatology (Oxford, England) [Rheumatology (Oxford)] 2024 Sep 01; Vol. 63 (9), pp. 2578-2589.
DOI:	10.1093/rheumatology/keae320
Abstrakt:	Objectives: 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. Methods: 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). Results: 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. Conclusion: FTY720 attenuated renal injury in EAV through upregulating FAO via the PPARα-CPT1a pathway in neutrophils, offering potential immunometabolic targets in AAV treatment. (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)
Databáze:	MEDLINE
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