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.
References
1.
Walport MJ: Complement. First of two parts. N Engl J Med 2001;344:1058-1066.
2.
Fearon DT, Austen KF: Properdin: binding to C3b and stabilization of the C3b-dependent C3 convertase. J Exp Med 1975;142:856-863.
3.
Hourcade DE: The role of properdin in the assembly of the alternative pathway C3 convertases of complement. J Biol Chem 2006;281:2128-2132.
4.
Kemper C, Atkinson JP, Hourcade DE: Properdin: emerging roles of a pattern-recognition molecule. Annu Rev Immunol 2010;28:131-155.
5.
Xu W, Berger SP, Trouw LA, de Boer HC, Schlagwein N, Mutsaers C, Daha MR, van Kooten C: Properdin binds to late apoptotic and necrotic cells independently of C3b and regulates alternative pathway complement activation. J Immunol 2008;180:7613-7621.
6.
Kemper C, Mitchell LM, Zhang L, Hourcade DE: The complement protein properdin binds apoptotic T cells and promotes complement activation and phagocytosis. Proc Natl Acad Sci USA 2008;105:9023-9028.
7.
Camous L, Roumenina L, Bigot S, Brachemi S, Fremeaux-Bacchi V, Lesavre P, Halbwachs-Mecarelli L: Complement alternative pathway acts as a positive feedback amplification of neutrophil activation. Blood 2011;117:1340-1349.
8.
Botto M, Lissandrini D, Sorio C, Walport MJ: Biosynthesis and secretion of complement component (C3) by activated human polymorphonuclear leukocytes. J Immunol 1992;149:1348-1355.
9.
Okuda T: Murine polymorphonuclear leukocytes synthesize and secrete the third component and factor B of complement. Int Immunol 1991;3:293-296.
10.
Wirthmueller U, Dewald B, Thelen M, Schafer MK, Stover C, Whaley K, North J, Eggleton P, Reid KB, Schwaeble WJ: Properdin, a positive regulator of complement activation, is released from secondary granules of stimulated peripheral blood neutrophils. J Immunol 1997;158:4444-4451.
11.
Venge P, Olsson I: Cationic proteins of human granulocytes. 6. Effects on the complement system and mediation of chemotactic activity. J Immunol 1975;115:1505-1508.
12.
Shingu M, Nonaka S, Nishimukai H, Nobunaga M, Kitamura H, Tomo-Oka K: Activation of complement in normal serum by hydrogen peroxide and hydrogen peroxide-related oxygen radicals produced by activated neutrophils. Clin Exp Immunol 1992;90:72-78.
13.
Vogt W: Complement activation by myeloperoxidase products released from stimulated human polymorphonuclear leukocytes. Immunobiology 1996;195:334-346.
14.
Xiao H, Schreiber A, Heeringa P, Falk RJ, Jennette JC: Alternative complement pathway in the pathogenesis of disease mediated by anti-neutrophil cytoplasmic autoantibodies. Am J Pathol 2007;170:52-64.
15.
Ballieux BE, Zondervan KT, Kievit P, Hagen EC, van Es LA, van der Woude FJ, Daha MR: Binding of proteinase 3 and myeloperoxidase to endothelial cells: ANCA-mediated endothelial damage through ADCC? Clin Exp Immunol 1994;97:52-60.
16.
Bjornson AB, Michael JG: Factors in human serum promoting phagocytosis of Pseudomonas aeruginosa. 1. Interaction of opsonins with the bacterium. J Infect Dis 1974;130(suppl):S119-S126.
17.
Pepys MB, Butterworth AE: Inhibition by C3 fragments of C3-dependent rosette formation and antigen-induced lymphocyte transformation. Clin Exp Immunol 1974;18:273-282.
18.
Gaarkeuken H, Siezenga MA, Zuidwijk K, van Kooten C, Rabelink TJ, Daha MR, Berger SP: Complement activation by tubular cells is mediated by properdin binding. Am J Physiol Renal Physiol 2008;295:F1397-F1403.
19.
Kallenberg CG, Heeringa P: Complement is crucial in the pathogenesis of ANCA-associated vasculitis. Kidney Int 2013;83:16-18.
20.
Maison CM, Villiers CL, Colomb MG: Proteolysis of C3 on U937 cell plasma membranes. Purification of cathepsin G. J Immunol 1991;147:921-926.
21.
Kessenbrock K, Krumbholz M, Schonermarck U, Back W, Gross WL, Werb Z, Grone HJ, Brinkmann V, Jenne DE: Netting neutrophils in autoimmune small-vessel vasculitis. Nat Med 2009;15:623-625.
22.
Hewins P, Morgan MD, Holden N, Neil D, Williams JM, Savage CO, Harper L: IL-18 is upregulated in the kidney and primes neutrophil responsiveness in ANCA-associated vasculitis. Kidney Int 2006;69:605-615.
23.
Xing GQ, Chen M, Liu G, Heeringa P, Zhang JJ, Zheng X, E J, Kallenberg CG, Zhao MH: Complement activation is involved in renal damage in human antineutrophil cytoplasmic autoantibody associated pauci-immune vasculitis. J Clin Immunol 2009;29:282-291.
24.
Gou SJ, Yuan J, Chen M, Yu F, Zhao MH: Circulating complement activation in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis. Kidney Int 2013;83:129-137.
© 2013 S. Karger AG, Basel
2013
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.
