Dysregulated neutrophil responses and neutrophil extracellular trap formation and degradation in PAPA syndrome.
Dysregulated neutrophil responses and neutrophil extracellular trap formation and degradation in PAPA syndrome.
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DOI：
10.1136/annrheumdis-2018-213746
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发表时间：
2018-12
影响因子：
27.4
通讯作者：
Kaplan MJ
中科院分区：
文献类型：
--
作者：
Mistry P;Carmona-Rivera C;Ombrello AK;Hoffmann P;Seto NL;Jones A;Stone DL;Naz F;Carlucci P;Dell'Orso S;Gutierrez-Cruz G;Sun HW;Kastner DL;Aksentijevich I;Kaplan MJ
化脓性关节炎、坏疽脓皮病和痤疮(PAPA)综合征的特征是无菌关节炎发作并伴有中性粒细胞浸润和白介素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(NETs)在PAPA发病机制中的作用。用流式细胞仪检测中性粒细胞和低密度粒细胞(LDGs)的数量。用ELISA法测定循环中的NETs，并检测Papa血清对NETs的降解能力。评估Papa中性粒细胞来源的Net激活巨噬细胞的能力。对皮肤活检组织进行Net和中性粒细胞基因特征分析。PAPA受试者循环低密度脂蛋白升高。与对照中性粒细胞相比，Papa中性粒细胞和LDGs表现出更强的网状形成。爸爸血清显示Net的降解受损，这可用外源DNase1纠正。重组人IL-1β可诱导PAPA中性粒细胞形成网状结构，但不能诱导健康对照中性粒细胞形成Net。健康对照中性粒细胞中的Net形成是由Papa血清诱导的，这一作用可被IL-1受体拮抗剂Anakinra抑制。来自Papa中性粒细胞和LDGs的Net刺激健康对照巨噬细胞释放IL-6。在PAPA患者的皮肤活检组织中检测到Net与组织IL-1β、IL-8和IL-17的升高有关。此外，在Papa皮肤中检测到LDG基因特征。Papa综合征的特征是净形成和降解的失衡，这可能会增加这些结构在体内的半衰期，从而促进炎症。Anakinra改善了PAPA中的网络形成，这一发现支持了IL-1信号在这种疾病中加剧中性粒细胞反应中的作用。这项研究还强调了PAPA中可能致病的其他炎症途径，包括IL-17和IL-6，这些结果可能有助于指导这种严重且往往难以治疗的疾病的新治疗方法。
Pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome is characterized 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 (NETs) in the pathogenesis of PAPA. Neutrophils and low-density granulocytes (LDGs) 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 analyzed for NETs and neutrophil gene signatures. Circulating LDGs are elevated in PAPA subjects. PAPA neutrophils and LDGs display enhanced NET formation compared to control neutrophils. PAPA sera exhibit impaired NET’s 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 PAPA patients in association with increased tissue IL-1β, IL-8 and IL-17. Furthermore, LDG gene signatures are detected in PAPA skin. PAPA syndrome is characterized 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 signaling 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 to guide new therapeutic approaches in this severe and often treatment-refractory condition.
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影响因子：
2.8
作者：
Manukyan, Gayane;Petrek, Martin;Boyajyan, Anna
通讯作者：
Boyajyan, Anna
DOI：
10.4049/jimmunol.1100123
发表时间：
2011-07-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Lin AM;Rubin CJ;Khandpur R;Wang JY;Riblett M;Yalavarthi S;Villanueva EC;Shah P;Kaplan MJ;Bruce AT
通讯作者：
Bruce AT
影响因子：
27.4
作者：
Knight JS;Subramanian V;O'Dell AA;Yalavarthi S;Zhao W;Smith CK;Hodgin JB;Thompson PR;Kaplan MJ
通讯作者：
Kaplan MJ
影响因子：
5.5
作者：
Cowland, JB;Borregaard, N
通讯作者：
Borregaard, N
影响因子：
--
作者：
HACBARTH, E;KAJDACSYBALLA, A
通讯作者：
KAJDACSYBALLA, A