Völlger Lena, Akong-Moore Kathryn, Cox Linda, Goldmann Oliver, Wang Yanming, Schäfer Simon T, Naim Hassan Y, Nizet Victor, von Köckritz-Blickwede Maren
Department of Physiological Chemistry, University of Veterinary Medicine Hannover, 30559 Hannover, Germany.
Department of Pediatrics, UCSD School of Medicine, San Diego, La Jolla, CA 9500, U.S.A.
Biosci Rep. 2016 May 20;36(3). doi: 10.1042/BSR20160031. Print 2016 Jul.
Neutrophil extracellular trap (NET) formation is a significant innate immune defense mechanism against microbial infection that complements other neutrophil functions including phagocytosis and degranulation of antimicrobial peptides. NETs are decondensed chromatin structures in which antimicrobial components (histones, antimicrobial peptides and proteases) are deployed and mediate immobilization of microbes. Here we describe an effect of iron chelation on the phenotype of NET formation. Iron-chelating agent desferrioxamine (DFO) showed a modest but significant induction of NETs by freshly isolated human neutrophils as visualized and quantified by immunocytochemistry against histone-DNA complexes. Further analyses revealed that NET induction by iron chelation required NADPH-dependent production of reactive oxygen species (ROS) as well as protease and peptidyl-arginine-deiminase 4 (PAD4) activities, three key mechanistic pathways previously linked to NET formation. Our results demonstrate that iron chelation by DFO contributes to the formation of NETs and suggest a target for pharmacological manipulation of NET activity.
中性粒细胞胞外诱捕网（NET）形成是一种重要的针对微生物感染的固有免疫防御机制，它补充了中性粒细胞的其他功能，包括吞噬作用和抗菌肽的脱颗粒。NET是解聚的染色质结构，其中抗菌成分（组蛋白、抗菌肽和蛋白酶）被部署并介导微生物的固定。在这里，我们描述了铁螯合对NET形成表型的影响。通过针对组蛋白-DNA复合物的免疫细胞化学可视化和定量分析，铁螯合剂去铁胺（DFO）显示出由新鲜分离的人中性粒细胞适度但显著地诱导NETs。进一步分析表明，铁螯合诱导NET需要依赖NADPH的活性氧（ROS）产生以及蛋白酶和肽基精氨酸脱亚氨酶4（PAD4）活性，这是先前与NET形成相关的三个关键机制途径。我们的结果表明，DFO的铁螯合作用有助于NETs的形成，并提示了一个对NET活性进行药理操纵的靶点。
