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Upregulation of Proinflammatory Bradykinin Peptides in Systemic Lupus Erythematosus and Rheumatoid Arthritis
The Journal of Immunology ( IF 4.4 ) Pub Date : 2020-06-15 , DOI: 10.4049/jimmunol.1801167
Kamala Vanarsa 1 , Jared Henderson 1 , Sanam Soomro 1 , Ling Qin 2 , Ting Zhang 1 , Nicole Jordan 3 , Chaim Putterman 3, 4, 5 , Irene Blanco 3 , Ramesh Saxena 6 , Chandra Mohan 7
Affiliation  

Key Points Serum BK-des-arg-9 is significantly elevated in mice and patients with lupus. A similar but less pronounced increase is also noted in RA serum. Increased conversion of BK to proinflammatory BK-des-arg-9 may mediate nephritis. Visual Abstract Our recent study has implicated bradykinin (BK) signaling as being of pathogenic importance in lupus. This study aims to investigate the biomarker potential of BK peptides, BK and BK-des-arg-9, in lupus and other rheumatic autoimmune diseases. Sera from systemic lupus erythematosus (SLE) patients and healthy subjects were screened for BK and BK-des-arg-9 by liquid chromatography–mass spectrometry metabolomics. Serum from 6-mo-old C57BL/6 mice and three murine lupus strains were also screened for the two peptides by metabolomics. Given the promising initial screening results, validation of these two peptides was next conducted using multiple reaction monitoring in larger patient cohorts. In initial metabolomics screening, BK-des-arg-9 was 22-fold higher in SLE serum and 106-fold higher in mouse lupus serum compared with healthy controls. In validation assays using multiple reaction monitoring and quadrupole time-of-flight mass spectrometry, BK and BK-des-arg-9 showed significant elevations in SLE serum compared with controls (p < 0.0001; area under the curve = 0.79–0.88), with a similar but less pronounced increase being noted in rheumatoid arthritis serum. Interestingly, increased renal SLE disease activity index in lupus patients was associated with reduced circulating BK-des-arg-9, and the reasons for this remain to be explored. To sum, increased conversion of BK to the proinflammatory metabolite BK-des-arg-9 appears to be a common theme in systemic rheumatic diseases. Besides serving as an early marker for systemic autoimmunity, independent studies also show that this metabolic axis may also be a pathogenic driver and therapeutic target in lupus.

中文翻译:

系统性红斑狼疮和类风湿关节炎中促炎缓激肽的上调

关键点血清 BK-des-arg-9 在小鼠和狼疮患者中显着升高。在 RA 血清中也注意到类似但不太明显的增加。BK 向促炎性 BK-des-arg-9 的转化增加可能介导肾炎。视觉摘要 我们最近的研究表明缓激肽 (BK) 信号传导在狼疮中具有重要的致病性。本研究旨在研究 BK 肽 BK 和 BK-des-arg-9 在狼疮和其他风湿性自身免疫性疾病中的生物标志物潜力。通过液相色谱-质谱代谢组学对系统性红斑狼疮 (SLE) 患者和健康受试者的血清进行 BK 和 BK-des-arg-9 筛查。还通过代谢组学筛选了来自 6 个月大的 C57BL/6 小鼠和三种鼠狼疮菌株的血清中的两种肽。鉴于有希望的初步筛选结果,接下来在更大的患者队列中使用多反应监测对这两种肽进行了验证。在初始代谢组学筛选中,与健康对照组相比,SLE 血清中的 BK-des-arg-9 高 22 倍,小鼠狼疮血清中的 BK-des-arg-9 高 106 倍。在使用多反应监测和四极杆飞行时间质谱法的验证分析中,与对照相比,BK 和 BK-des-arg-9 显示 SLE 血清显着升高(p < 0.0001;曲线下面积 = 0.79-0.88),在类风湿性关节炎血清中注意到类似但不太明显的增加。有趣的是,狼疮患者肾脏 SLE 疾病活动指数增加与循环 BK-des-arg-9 减少有关,其原因仍有待探索。总结,BK 向促炎代谢物 BK-des-arg-9 的转化增加似乎是系统性风湿性疾病的一个共同主题。除了作为系统性自身免疫的早期标志物外,独立研究还表明,这种代谢轴也可能是狼疮的致病驱动因素和治疗靶点。
更新日期:2020-06-15
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