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O) 2 Platelets Mediated by Properdin and C3(H Complement Activation on Stimulated Identification of a Novel Mode Of Identification of a Novel Mode of Complement Activation on Stimulated Platelets Mediated by Properdin and C3(H2 O) This information is current as of October 1, 2021. Gurpanna Saggu, Claudio Cortes, Heather N. Emch, Galia Ramirez, Randall G. Worth and Viviana P. Ferreira J Immunol 2013; 190:6457-6467; Prepublished online 15 May 2013; doi: 10.4049/jimmunol.1300610 Downloaded from http://www.jimmunol.org/content/190/12/6457 Supplementary http://www.jimmunol.org/content/suppl/2013/05/17/jimmunol.130061 Material 0.DC1 http://www.jimmunol.org/ References This article cites 72 articles, 37 of which you can access for free at: http://www.jimmunol.org/content/190/12/6457.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on October 1, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2013 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Identification of a Novel Mode of Complement Activation on Stimulated Platelets Mediated by Properdin and C3(H2O) Gurpanna Saggu,*,1 Claudio Cortes,*,†,1 Heather N. Emch,* Galia Ramirez,*,‡ Randall G. Worth,* and Viviana P. Ferreira* Elevated numbers of activated platelets circulate in patients with chronic inflammatory diseases, including atherosclerosis and coronary disease. Activated platelets can activate the complement system. Although complement activation is essential for immune responses and removal of spent cells from circulation, it also contributes to inflammation and thrombosis, especially in patients with defective complement regulation. Proinflammatory activated leukocytes, which interact directly with platelets in response to vas- cular injury, are among the main sources of properdin, a positive regulator of the alternative pathway. The role of properdin in complement activation on stimulated platelets is unknown. Our data show that physiological forms of human properdin bind di- rectly to human platelets after activation by strong agonists in the absence of C3, and bind nonproportionally to surface CD62P Downloaded from expression. Activation of the alternative pathway on activated platelets occurs when properdin is on the surface and recruits C3b or C3(H2O) to form C3b,Bb or a novel cell-bound C3 convertase [C3(H2O),Bb], which normally is present only in the fluid phase. Alternatively, properdin can be recruited by C3(H2O) on the platelet surface, promoting complement activation. Inhibition of factor H–mediated cell surface complement regulation significantly increases complement deposition on activated platelets with surface properdin. Finally, properdin released by activated neutrophils binds to activated platelets. Altogether, these data suggest novel molecular mechanisms for alternative pathway activation on stimulated platelets that may contribute to localization of http://www.jimmunol.org/ inflammation at sites of vascular injury and thrombosis. The Journal of Immunology, 2013, 190: 6457–6467. latelets are small and anucleate circulating particles that ease, have a higher number of activated platelets (4, 5) and platelet/ derive from bone marrow megakaryocytes. These cells play leukocyte aggregates (6) circulating in the blood. P a central role in hemostasis, inflammation, and disease- Stimulated platelets activate the complement system on or near related thrombosis, because they are the first circulating blood their surface (7–12). In general, normal inflammatory processes cells that, upon activation, rapidly adhere to tissue, to leukocytes require complement activation for an effective immune response, as well as for efficient removal of spent cells from circulation. In (recruitment), and to one another in response to vascular injury (1, by guest on October 1, 2021 2). However, excessive or inadvertent platelet activation is com- pathological acute and chronic inflammatory diseases (e.g., sys- mon at sites of endothelial damage, underlying many cardiovas- temic lupus erythematosus, cancer, atherosclerosis, ischemia/re- cular disorders, such as myocardial infarction, unstable angina, and perfusion injury, neuroinflammation), excessive complement acti- stroke (3). Patients with chronic inflammatory conditions, such as vation contributes to tissue damage and leads to elevated release unstable atherosclerosis, hypercholesterolemia, and coronary dis- of proinflammatory by-products (e.g., C5a, C3a) and C5b-9 end product (membrane attack complex [MAC]) (13), which, in turn, participate in leukocyte recruitment, vascular inflammation, platelet activation, and thrombosis (14, 15). Thus, understanding the mo- *Department of Medical Microbiology and Immunology, College of Medicine and lecular mechanisms by which complement activates on stimulated † Life Sciences, University of Toledo, Toledo, OH 43614; Department of Molecular platelets becomes essential for understanding its role in platelet- Sciences, Medical University of the Americas, Charlestown, Nevis, West Indies; and ‡Department of Preventive Animal Medicine, Faculty of Veterinary Medicine, Uni- mediated physiology and disease pathogenesis. Both the classical versity of Chile, Santiago, Chile 8820808 (7) and the alternative pathways (9) were shown to activate on the 1G.S. and C.C. contributed equally to this work. platelet surface, despite the presence of complement regulatory Received for publication March 5, 2013. Accepted for publication April 9, 2013. proteins. In addition, individuals with paroxysmal nocturnal This work was supported by National Institutes of Health Grant 1P30HL101317-01, hemoglobinuria or atypical hemolytic uremic syndrome (aHUS), American Heart Association Grant 12GRNT10240003, and the University of Toledo diseases in which the activity of one or more complement regula- DeArce-Koch Memorial Endowment Fund (all to V.P.F.). tory proteins (e.g., factor H, CD59, CD55, CD46) is impaired (16, Address correspondence and reprint requests to Dr. Viviana P. Ferreira, Department 17), have exacerbated complement activation on their platelets of Medical Microbiology and Immunology, College of Medicine and Life Sciences, University of Toledo, 3000 Arlington Avenue, Mail Stop 1021, Health Education (18, 19). However, recent studies indicate that complement acti- Building 259C, Toledo, OH 43614. E-mail address: [email protected] vates in the microenvironment surrounding the stimulated platelet The online version of this article contains supplemental material. upon release of chondroitin sulfate A (10), but not on the platelet Abbreviations used in this article: aHUS, atypical hemolytic uremic syndrome; COX, surface, when complement regulation is intact (11). Therefore, the cyclooxygenase; ESC3b, C3b-coated sheep erythrocyte; GAG, glycosaminoglycan; mechanisms by which complement activates on stimulated platelets MAC, membrane attack complex; NHS, normal human serum; P2, dimeric form of remain controversial. properdin; P3, trimeric form of properdin; P4, tetrameric form of properdin; PMN, polymorphonuclear cell; Pn, nonphysiological aggregated form of properdin; rH19- The alternative pathway of complement represents a true safe- 20, recombinant protein consisting of domains 19–20 of factor H; RT, room temper- guard system of the human host and is initiated in the fluid phase ature; Tyrode/PGE/Hep buffer, Tyrode’s buffer containing PGE and heparin. 1 by the spontaneous hydrolysis of the thioester bond in C3 to pro- Copyright Ó 2013 by The American Association of Immunologists, Inc. 0022-1767/13/$16.00 duce C3(H2O), which is functionally and structurally similar to C3b www.jimmunol.org/cgi/doi/10.4049/jimmunol.1300610 6458 PROPERDIN BINDS PLATELETS AND ACTIVATES COMPLEMENT (20) (tickover theory; reviewed in Ref. 21). Binding of factor B Tyrode/PGE/Hep buffer (Tyrode’s buffer containing 1 mM PGE1 and 2 IU/ ml heparin); Gelatin veronal buffer (5 mM veronal, 145 mM NaCl, 0.004% to C3(H2O) in the presence of factor D allows the generation of NaN3, 0.1% gelatin); PBS (10 mM sodium phosphate, 140 mM NaCl, an unstable fluid-phase C3 convertase [C3(H2O),Bb], which has 0.02% NaN3 [pH 7.4]); Mono S buffer A (50 mM sodium phosphate [pH the ability to digest C3 to generate C3b fragments (22). The C3b 6]); Mono S buffer B (50 mM sodium phosphate, 0.5 M NaCl [pH 6]); and fragments can bind to any nearby surface with exposed amino or Mg-EGTA buffer stock (0.1 M MgCl2, 0.1 M EGTA [pH 7.3]). hydroxyl groups (23). Factor B can then bind to this membrane- Abs bound C3b and be cleaved by factor D to generate the membrane- bound alternative pathway C3 convertase (C3b,Bb) (24). Properdin, The following murine mAbs were used in this study: IgG1 anti-human the only known positive regulator of the alternative pathway, sta- properdin (#1; Quidel), IgG1 isotype control (eBioscience), IgG1 anti- human C3/C3b (Cedarlane Laboratories), PE-conjugated IgG1 anti-human bilizes the C3b,Bb complex, increasing its t1/2
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