Department of Medicine, Division of Rheumatology, University of Washington, Seattle, WA, USA.
Division of Rheumatology, University of Colorado-Denver, Aurora, CO, USA.
J Autoimmun. 2021 May;119:102630. doi: 10.1016/j.jaut.2021.102630. Epub 2021 Mar 10.
Literature suggests that neutrophils of patients with rheumatoid arthritis (RA) are primed to respond to N-formyl methionine group (formylated peptides). Animal models indicate that formylated peptides contribute to joint damage via neutrophil recruitment and inflammation in joints. Non-steroidal anti-inflammatory drugs are also known to inhibit formyl peptide-induced neutrophil activation. The predominant source of formylated peptides in sterile inflammatory conditions like RA is mitochondria, organelles with prokaryotic molecular signatures. However, there is no direct evidence of mitochondrial formyl peptides (mtNFPs) in the circulation of patients with RA and their potential role in neutrophil-mediated inflammation in RA, including their clinical significance.
Levels of mtNFPs (total fMet, MT-ND6) were analyzed using ELISA in plasma and serum obtained from patients in 3 cross-sectional RA cohorts (n = 275), a longitudinal inception cohort (n = 192) followed for a median of 8 years, and age/gender-matched healthy controls (total n = 134). Neutrophil activation assays were done in the absence or presence of formyl peptide receptor 1 (FPR1) inhibitor cyclosporine H.
Elevated levels of total fMet were observed in the circulation of patients with RA as compared to healthy controls (p < 0.0001) associating with disease activity and could distinguish patients with the active disease from patients with inactive disease or patients in remission. Baseline levels of total fMet correlated with current and future joint involvement, respectively and predicted the development of rheumatoid nodules (OR = 1.2, p = 0.04). Further, total fMet levels improved the prognostic ability of ACPA in predicting erosive disease (OR of 7.9, p = 0.001). Total fMet levels correlated with markers of inflammation and neutrophil activation. Circulating mtNFPs induced neutrophil activation in vitro through FPR1-dependent mechanisms.
Circulating mtNFPs could be novel biomarkers of disease monitoring and prognosis for RA and in investigating neutrophil-mediated inflammation in RA. We propose, FPR1 as a novel therapeutic target for RA.
文献表明，类风湿关节炎（RA）患者的中性粒细胞对外源 N-甲酰甲硫氨酸基团（甲酰化肽）的反应能力增强。动物模型表明，甲酰化肽通过中性粒细胞募集和关节炎症导致关节损伤。非甾体抗炎药也已知能抑制甲酰肽诱导的中性粒细胞激活。在无菌性炎症条件下，如 RA，甲酰肽的主要来源是具有原核分子特征的细胞器——线粒体。然而，目前尚无 RA 患者循环中存在线粒体甲酰肽（mtNFPs）的直接证据，也没有关于其在 RA 中中性粒细胞介导的炎症中的潜在作用及其临床意义的直接证据。
采用 ELISA 法检测来自 3 个横断面 RA 队列（n=275）、192 个纵向发病队列（中位随访 8 年，n=192）患者的血浆和血清中 mtNFPs（总 fMet、MT-ND6）水平，以及年龄和性别匹配的健康对照者（总 n=134）。在不存在或存在甲酰肽受体 1（FPR1）抑制剂环孢素 H 的情况下进行中性粒细胞激活测定。
与健康对照组相比，RA 患者的循环总 fMet 水平升高（p<0.0001），与疾病活动度相关，并可将活动期患者与非活动期患者或缓解期患者区分开来。基线总 fMet 水平与当前和未来的关节受累分别相关，并预测类风湿结节的发生（OR=1.2，p=0.04）。此外，总 fMet 水平提高了 ACPA 预测侵蚀性疾病的预后能力（OR 为 7.9，p=0.001）。总 fMet 水平与炎症和中性粒细胞激活标志物相关。循环 mtNFPs 通过 FPR1 依赖机制诱导体外中性粒细胞激活。
循环 mtNFPs 可能是 RA 疾病监测和预后的新型生物标志物，也可用于研究 RA 中中性粒细胞介导的炎症。我们提出，FPR1 可能是 RA 的一个新的治疗靶点。
