title: Immobilized immune complexes induce neutrophil extracellular trap release by human neutrophil granulocytes via FcγRIIIB and Mac-1.
abstract: Canonical neutrophil antimicrobial effector mechanisms, such as degranulation, production of reactive oxygen species, and release of neutrophil extracellular traps (NETs), can result in severe pathology. Activation of neutrophils through immune complexes (ICs) plays a central role in the pathogenesis of many autoimmune inflammatory diseases. In this study, we report that immobilized ICs (iICs), which are hallmarks of several autoimmune diseases, induce the release of NETs from primary human neutrophils. The iIC-induced NET formation was found to require production of reactive oxygen species by NADPH oxidase and myeloperoxidase and to be mediated by FcγRIIIb. Blocking of the β2 integrin macrophage-1 Ag but not lymphocyte function-associated Ag-1 abolished iIC-induced NET formation. This suggests that FcγRIIIb signals in association with macrophage-1 Ag. As intracellular signaling pathways involved in iIC-induced NET formation we identified the tyrosine kinase Src/Syk pathway, which downstream regulates the PI3K/Akt, p38 MAPK, and ERK1/2 pathways. To our knowledge, the present study shows for the first time that iICs induce NET formation. Thus, we conclude that NETs contribute to pathology in autoimmune inflammatory disorders associated with surface-bound ICs.
authors.affiliation: Institute for Medical Microbiology and Hygiene, University of Lübeck, D-23538 Lübeck, Germany; and Martina.Behnen-Haerer@uksh.de.
authors.forename: Martina
authors.initials: M
authors.lastname: Behnen
authors.affiliation: Institute for Medical Microbiology and Hygiene, University of Lübeck, D-23538 Lübeck, Germany; and.
authors.forename: Christoph
authors.initials: C
authors.lastname: Leschczyk
authors.affiliation: Institute for Medical Microbiology and Hygiene, University of Lübeck, D-23538 Lübeck, Germany; and.
authors.forename: Sonja
authors.initials: S
authors.lastname: Möller
authors.affiliation: Institute for Medical Microbiology and Hygiene, University of Lübeck, D-23538 Lübeck, Germany; and.
authors.forename: Tobit
authors.initials: T
authors.lastname: Batel
authors.affiliation: Institute of Anatomy, University of Lübeck, D-23538 Lübeck, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Klinger
authors.affiliation: Institute for Medical Microbiology and Hygiene, University of Lübeck, D-23538 Lübeck, Germany; and.
authors.forename: Werner
authors.initials: W
authors.lastname: Solbach
authors.affiliation: Institute for Medical Microbiology and Hygiene, University of Lübeck, D-23538 Lübeck, Germany; and.
authors.forename: Tamás
authors.initials: T
authors.lastname: Laskay
mesh_terms: D000632:Aminopyrine / Q000494:pharmacology; D000936:Antigen-Antibody Complex / Q000276:immunology*; D000975:Antioxidants / Q000494:pharmacology; D001205:Ascorbic Acid / Q000494:pharmacology; D001327:Autoimmune Diseases / Q000276:immunology; D002070:Butadienes / Q000494:pharmacology; D040881:CD11a Antigen / Q000378:metabolism; D018821:CD18 Antigens / Q000378:metabolism; D015550:Cell Degranulation; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D058851:GPI-Linked Proteins / Q000276:immunology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007249:Inflammation / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology; D016177:Macrophage-1 Antigen / Q000276:immunology* / Q000378:metabolism; D019804:Mesalamine / Q000494:pharmacology; D018375:Neutrophil Activation / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology*; D009570:Nitriles / Q000494:pharmacology; D009861:Onium Compounds / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D017452:Receptors, IgG / Q000037:antagonists & inhibitors / Q000276:immunology*; D000072377:Syk Kinase; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000276:immunology
chemical_list: C412373:AG 1879; D000936:Antigen-Antibody Complex; D000975:Antioxidants; D002070:Butadienes; D040881:CD11a Antigen; D018821:CD18 Antigens; C489017:FCGR1A protein, human; C428200:FCGR3B protein, human; C080568:Fc gamma receptor IIA; D058851:GPI-Linked Proteins; D007093:Imidazoles; D047908:Intracellular Signaling Peptides and Proteins; D016169:Lymphocyte Function-Associated Antigen-1; D016177:Macrophage-1 Antigen; D009570:Nitriles; D009861:Onium Compounds; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D017452:Receptors, IgG; C113580:U 0126; D000632:Aminopyrine; D019804:Mesalamine; C007517:diphenyleneiodonium; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; D001205:Ascorbic Acid