title: Myeloperoxidase directs properdin-mediated complement activation.
abstract: Neutrophils and complement are key members of innate immunity. The alternative pathway (AP) of complement consists of C3, factor B, factor D and properdin, which amplifies AP activation. AP has been implicated in many neutrophil-mediated diseases, such as anti-neutrophil cytoplasmic antibody-associated vasculitis. The exact mechanism by which the AP and neutrophils interact remains largely unstudied. We investigated the ability of the AP to interact with neutrophil components which can be exposed and released upon activation. Our studies focused on neutrophil enzymes, including myeloperoxidase (MPO), proteinase 3 (PR3), azurocidin, elastase, lysozyme and cathepsin G. All enzymes except for azurocidin were able to bind properdin. However, only MPO could induce C3 activation. MPO mediated AP complement activation in the presence of MgEGTA compared to the EDTA control. This activation resulted in C3 deposition and required properdin to occur. Furthermore, we could show that MPO binds properdin directly, which then serves as a focus for AP activation. In summary, properdin can directly interact with neutrophil components. MPO demonstrates the ability to activate the AP which is dependent on properdin. Finally, MPO is capable of inducing properdin-initiated C3 and C5b-9 deposition in vitro.
authors.affiliation: Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Joseph
authors.initials: J
authors.lastname: O'Flynn
authors.forename: Karen O
authors.initials: KO
authors.lastname: Dixon
authors.forename: Maria C
authors.initials: MC
authors.lastname: Faber Krol
authors.forename: Mohamed R
authors.initials: MR
authors.lastname: Daha
authors.forename: Cees
authors.initials: C
authors.lastname: van Kooten
mesh_terms: D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / Q000276:immunology*; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism; D001798:Blood Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D056649:Cathepsin G / Q000378:metabolism; D003176:Complement C3 / Q000378:metabolism; D015938:Complement Membrane Attack Complex / Q000378:metabolism; D003170:Complement Pathway, Alternative; D006801:Humans; D007113:Immunity, Innate; D009113:Muramidase / Q000378:metabolism; D053146:Myeloblastin / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology*; D010196:Pancreatic Elastase / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism*; D011414:Properdin / Q000378:metabolism*; D011485:Protein Binding
chemical_list: C062991:AZU1 protein, human; D023181:Antimicrobial Cationic Peptides; D001798:Blood Proteins; D002352:Carrier Proteins; D003176:Complement C3; D015938:Complement Membrane Attack Complex; D011414:Properdin; D009195:Peroxidase; D009113:Muramidase; D056649:Cathepsin G; D010196:Pancreatic Elastase; D053146:Myeloblastin