Circulating neutrophil extracellular trap-forming neutrophils in rheumatoid arthritis exacerbation are majority dual endothelin-1/signal peptide receptor+ subtype.

IF 3.4 3区 医学 Q3 IMMUNOLOGY Clinical and experimental immunology Pub Date : 2024-10-16 DOI:10.1093/cei/uxae072
Andrew L Cross, Helen L Wright, Jacqueline Choi, Steven W Edwards, Nelson Ruiz-Opazo, Victoria L M Herrera
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Abstract

Neutrophil extracellular traps (NETs) are associated with rheumatoid arthritis pathogenesis and severity. Since homeostatic NET-forming neutrophils [NET+Ns] have beneficial roles in defense against pathogens, their distinction from pro-injury [NET+N] subtypes is important, especially if they are to be therapeutically targeted. Having identified circulating, pro-injury DEspR+CD11b+[NET+Ns] in patients with neutrophilic secondary tissue injury, we determined whether DEspR+[NET+Ns] are present in rheumatoid arthritis (RA) flares. Whole blood samples of patients with RA flares on maintenance therapy (n = 6) were analyzed by flow cytometry (FCM) and immunofluorescence cytology followed by semi-automated quantitative confocal microscopy (qIFC). We assessed clinical parameters, levels of neutrophils and [NET+Ns], and plasma S100A8/A9. qIFC detected circulating DEspR+CD11b+neutrophils and [NET+Ns] in RA-flare patients but not healthy controls. DEspR+[NET+Ns] were positive for citrullinated histone H3 (citH3+), extruded DNA, decondensed but recognizable polymorphic nuclei, and [NET+N] doublet interactions in mostly non-ruptured NET-forming neutrophils. Circulating DNA+/DEspR+/CD11b+/citH3+microvesicles (netMVs) were observed. FCM detected increased %DEspR+CD11b+neutrophils and DEspR+ cell-cell doublets whose levels trended with DAS28 scores, as did plasma S100A8/A9 levels. This study identifies circulating DEspR+/CD11b+neutrophils and [NET+Ns] in RA-flare patients on maintenance therapy. Detection of circulating DEspR+citH3+[NET+Ns] and netMVs indicate a systemic neutrophilic source of citH3-antigen concordant with multi-joint RA pathogenesis. Increased S100A8/A9 alarmin levels are associated with cell injury and released upon NET-formation. As a ligand for TLR4, S100A8/A9 forms a positive feedback loop for TLR4-induced DEspR+neutrophils. These data identify DEspR+neutrophils and [NET+Ns] in RA pathogenesis as a potential biomarker and/or therapeutic target.

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类风湿性关节炎加重期的循环中性粒细胞胞外捕获器(NET)形成的中性粒细胞大多是内皮素-1/信号肽受体(DEspR)+双重亚型。
中性粒细胞胞外捕获物(NET)与类风湿性关节炎的发病机制和严重程度有关。由于平衡型NET形成的中性粒细胞[NET+Ns]在抵御病原体方面发挥有益作用,因此将它们与促损伤型[NET+N]亚型区分开来非常重要,尤其是如果要以它们为治疗目标的话。在中性粒细胞继发性组织损伤患者中发现了循环中的促损伤 DEspR+CD11b+ [NET+Ns]后,我们确定了 RA 病变中是否存在 DEspR+ [NET+Ns]。我们通过流式细胞术(FCM)和免疫荧光细胞学方法对接受维持治疗的 RA 发炎患者(6 人)的全血样本进行了分析,然后使用半自动定量共聚焦显微镜(qIFC)进行观察。我们评估了临床参数、中性粒细胞和[NET+Ns]水平以及血浆 S100A8/A9。qIFC 在 RA 发疹患者中检测到了循环中的 DEspR+CD11b+ 中性粒细胞和[NET+Ns],而健康对照组没有检测到。DEspR+[NET+Ns]对瓜氨酸组蛋白H3(citH3+)、挤出的DNA、解聚但可识别的多形性核以及[NET+N]双交互作用呈阳性,其中大部分是非破裂的NET形成的中性粒细胞。观察到循环 DNA+/DEspR+/CD11b+/citH3+ 微囊泡(netMVs)。FCM检测到%DEspR+CD11b+中性粒细胞和DEspR+细胞-细胞双倍体增加,其水平与DAS28评分呈趋势,血浆S100A8/A9水平也是如此。这项研究确定了接受维持治疗的 RA 发炎患者中的循环 DEspR+/CD11b+ 中性粒细胞和 [NET+Ns] 。循环中 DEspR+citH3+ [NET+Ns] 和 netMVs 的检测表明,citH3 抗原的系统性中性粒细胞来源与多关节 RA 发病机制一致。S100A8/A9 alarmin水平的增加与细胞损伤有关,并在NET形成时释放。作为 TLR4 的配体,S100A8/A9 对 TLR4 诱导的 DEspR+ 中性粒细胞形成正反馈回路。这些数据确定了 DEspR+ 中性粒细胞和[NET+Ns]在 RA 发病机制中是一种潜在的生物标记物和/或治疗靶点。
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来源期刊
CiteScore
8.40
自引率
2.20%
发文量
101
审稿时长
3-8 weeks
期刊介绍: Clinical & Experimental Immunology (established in 1966) is an authoritative international journal publishing high-quality research studies in translational and clinical immunology that have the potential to transform our understanding of the immunopathology of human disease and/or change clinical practice. The journal is focused on translational and clinical immunology and is among the foremost journals in this field, attracting high-quality papers from across the world. Translation is viewed as a process of applying ideas, insights and discoveries generated through scientific studies to the treatment, prevention or diagnosis of human disease. Clinical immunology has evolved as a field to encompass the application of state-of-the-art technologies such as next-generation sequencing, metagenomics and high-dimensional phenotyping to understand mechanisms that govern the outcomes of clinical trials.
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