Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, Maryland, USA.
Inflammatory Disease Section, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.
Ann Rheum Dis. 2018 Dec;77(12):1825-1833. doi: 10.1136/annrheumdis-2018-213746. Epub 2018 Aug 21.
Pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome is characterised by flares of sterile arthritis with neutrophil infiltrate and the overproduction of interleukin (IL)-1β. The purpose of this study was to elucidate the potential role of neutrophil subsets and neutrophil extracellular traps (NET) in the pathogenesis of PAPA.
Neutrophils and low-density granulocytes (LDG) were quantified by flow cytometry. Circulating NETs were measured by ELISA and PAPA serum was tested for the ability to degrade NETs. The capacity of NETs from PAPA neutrophils to activate macrophages was assessed. Skin biopsies were analysed for NETs and neutrophil gene signatures.
Circulating LDGs are elevated in PAPA subjects. PAPA neutrophils and LDGs display enhanced NET formation compared with control neutrophils. PAPA sera exhibit impaired NET degradation and this is corrected with exogenous DNase1. Recombinant human IL-1β induces NET formation in PAPA neutrophils but not healthy control neutrophils. NET formation in healthy control neutrophils is induced by PAPA serum and this effect is inhibited by the IL-1 receptor antagonist, anakinra. NETs from PAPA neutrophils and LDGs stimulate IL-6 release in healthy control macrophages. NETs are detected in skin biopsies of patients with PAPA syndrome in association with increased tissue IL-1β, IL-8 and IL-17. Furthermore, LDG gene signatures are detected in PAPA skin.
PAPA syndrome is characterised by an imbalance of NET formation and degradation that may enhance the half-life of these structures in vivo, promoting inflammation. Anakinra ameliorates NET formation in PAPA and this finding supports a role for IL-1 signalling in exacerbated neutrophil responses in this disease. The study also highlights other inflammatory pathways potentially pathogenic in PAPA, including IL-17 and IL-6, and these results may help guide new therapeutic approaches in this severe and often treatment-refractory condition.
化脓性关节炎、坏疽性脓皮病和痤疮（PAPA）综合征的特征是无菌性关节炎发作，伴有中性粒细胞浸润和白细胞介素（IL）-1β的过度产生。本研究的目的是阐明中性粒细胞亚群和中性粒细胞胞外陷阱（NET）在 PAPA 发病机制中的潜在作用。
通过流式细胞术定量中性粒细胞和低密度粒细胞（LDG）。通过 ELISA 测量循环 NET，测试 PAPA 血清降解 NET 的能力。评估来自 PAPA 中性粒细胞的 NET 激活巨噬细胞的能力。分析皮肤活检以评估 NET 和中性粒细胞基因特征。
PAPA 患者循环 LDG 升高。与对照中性粒细胞相比，PAPA 中性粒细胞和 LDG 显示增强的 NET 形成。PAPA 血清显示 NET 降解受损，外源性 DNase1 可纠正。重组人 IL-1β诱导 PAPA 中性粒细胞形成 NET，但不诱导健康对照中性粒细胞形成 NET。PAPA 血清诱导健康对照中性粒细胞形成 NET，IL-1 受体拮抗剂 anakinra 可抑制这种效应。NET 来自 PAPA 中性粒细胞和 LDG 刺激健康对照巨噬细胞释放 IL-6。在 PAPA 综合征患者的皮肤活检中检测到 NET，同时伴有组织中 IL-1β、IL-8 和 IL-17 的增加。此外，在 PAPA 皮肤中检测到 LDG 基因特征。
PAPA 综合征的特征是 NET 形成和降解失衡，这可能会增加这些结构在体内的半衰期，从而促进炎症。Anakinra 可改善 PAPA 中的 NET 形成，这一发现支持 IL-1 信号在该疾病中加剧中性粒细胞反应的作用。该研究还突出了 PAPA 中其他潜在的炎症途径，包括 IL-17 和 IL-6，这些结果可能有助于指导这种严重且通常治疗抵抗的疾病的新治疗方法。
