Myeloperoxidase Directs Properdin-Mediated Complement Activation

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-associa...

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Bibliographic Details
Published in:Journal of innate immunity 2014-01, Vol.6 (4), p.417-425
Main Authors: O'Flynn, Joseph, Dixon, Karen O., Faber Krol, Maria C., Daha, Mohamed R., van Kooten, Cees
Format: Article
Language:English
Subjects:
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis - immunology
Antimicrobial Cationic Peptides - metabolism
Blood Proteins - metabolism
Carrier Proteins - metabolism
Cathepsin G - metabolism
Complement C3 - metabolism
Complement Membrane Attack Complex - metabolism
Complement Pathway, Alternative
Humans
Immunity, Innate
Muramidase - metabolism
Myeloblastin - metabolism
Neutrophils - immunology
Pancreatic Elastase - metabolism
Peroxidase - metabolism
Properdin - metabolism
Protein Binding
Research Article
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Summary: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.
ISSN:1662-811X
1662-8128
DOI:10.1159/000356980