title: Iron-chelating agent desferrioxamine stimulates formation of neutrophil extracellular traps (NETs) in human blood-derived neutrophils.
abstract: 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.
authors.affiliation: Department of Physiological Chemistry, University of Veterinary Medicine Hannover, 30559 Hannover, Germany.
authors.forename: Lena
authors.initials: L
authors.lastname: Völlger
authors.affiliation: Department of Pediatrics, UCSD School of Medicine, San Diego, La Jolla, CA 9500, U.S.A.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Akong-Moore
authors.affiliation: Klinik für Anästhesiologie und Intensivmedizin, Universitätsklinikum Essen, Universität Duisburg-Essen, 45147 Essen, Germany Institut für Physiologie, Universität Duisburg-Essen, 45147 Essen, Germany.
authors.forename: Linda
authors.initials: L
authors.lastname: Cox
authors.affiliation: Infection Immunology Group, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Goldmann
authors.affiliation: Center for Eukaryotic Gene Regulation, Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, U.S.A.
authors.forename: Yanming
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Klinik für Anästhesiologie und Intensivmedizin, Universitätsklinikum Essen, Universität Duisburg-Essen, 45147 Essen, Germany Institut für Physiologie, Universität Duisburg-Essen, 45147 Essen, Germany.
authors.forename: Simon T
authors.initials: ST
authors.lastname: Schäfer
authors.affiliation: Department of Physiological Chemistry, University of Veterinary Medicine Hannover, 30559 Hannover, Germany.
authors.forename: Hassan Y
authors.initials: HY
authors.lastname: Naim
authors.affiliation: Department of Pediatrics, UCSD School of Medicine, San Diego, La Jolla, CA 9500, U.S.A. Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, U.S.A.
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
authors.affiliation: Department of Physiological Chemistry, University of Veterinary Medicine Hannover, 30559 Hannover, Germany Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, 30559 Hannover, Germany maren.von.koeckritz-blickwede@tiho-hannover.de.
authors.forename: Maren
authors.initials: M
authors.lastname: von Köckritz-Blickwede
mesh_terms: D002478:Cells, Cultured; D003676:Deferoxamine / Q000494:pharmacology*; D065206:Extracellular Traps / Q000187:drug effects* / Q000276:immunology / Q000382:microbiology; D006801:Humans; D007113:Immunity, Innate; D007502:Iron Chelating Agents / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology / Q000382:microbiology; D010447:Peptide Hydrolases / Q000276:immunology; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases / Q000276:immunology; D017382:Reactive Oxygen Species / Q000276:immunology
chemical_list: D007502:Iron Chelating Agents; D017382:Reactive Oxygen Species; D010447:Peptide Hydrolases; C000629235:PADI4 protein, human; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; D003676:Deferoxamine
keywords: extracellular traps; innate immunity; neutrophils