Objectives

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.

Methods

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.

Results

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.

Conclusions

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.

中文翻译：

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线粒体 N-甲酰甲硫氨酸肽与疾病活动相关，并有助于类风湿性关节炎患者的中性粒细胞活化

目标

文献表明，类风湿性关节炎 (RA) 患者的中性粒细胞已准备好对 N-甲酰甲硫氨酸基团（甲酰化肽）产生反应。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。还已知非甾体抗炎药可抑制甲酰肽诱导的中性粒细胞活化。在 RA 等无菌炎症条件下，甲酰化肽的主要来源是线粒体，即具有原核分子特征的细胞器。然而，没有直接证据表明线粒体甲酰肽 (mtNFP) 在 RA 患者的循环中以及它们在 RA 中性粒细胞介导的炎症中的潜在作用，包括它们的临床意义。

方法

mtNFPs 水平（总 fMet，MT-ND6）使用 ELISA 分析从 3 个横断面 RA 队列（n = 275）中的患者获得的血浆和血清中，纵向初始队列（n = 192）随后的中位数为 8年和年龄/性别匹配的健康对照（总 n = 134）。在不存在或存在甲酰肽受体 1 (FPR1) 抑制剂环孢菌素 H 的情况下进行中性粒细胞活化测定。

结果

与健康对照相比，在 RA 患者的循环中观察到总 fMet 水平升高（p < 0.0001），这与疾病活动相关，并且可以区分患有活动性疾病的患者与非活动性疾病患者或缓解患者。总 fMet 的基线水平分别与当前和未来的关节受累相关，并预测类风湿结节的发展（OR = 1.2，p = 0.04）。此外，总 fMet 水平提高了 ACPA 在预测糜烂性疾病方面的预后能力（OR 为 7.9，p = 0.001）。总 fMet 水平与炎症标志物和中性粒细胞活化相关。循环 mtNFPs通过 FPR1 依赖性机制在体外诱导中性粒细胞活化。

结论

循环中的 mtNFPs 可能是 RA 疾病监测和预后以及研究 RA 中中性粒细胞介导炎症的新型生物标志物。我们建议，FPR1 作为 RA 的新治疗靶点。