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Properdin-Mediated C5a Production Enhances Stable Binding of Platelets to Granulocytes in Human Whole Blood

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Properdin-Mediated C5a Production Enhances Stable Binding of Platelets to Granulocytes in Human Whole Blood Properdin-Mediated C5a Production Enhances Stable Binding of Platelets to Granulocytes in Human Whole Blood This information is current as Adam Z. Blatt, Gurpanna Saggu, Koustubh V. Kulkarni, of September 29, 2021. Claudio Cortes, Joshua M. Thurman, Daniel Ricklin, John D. Lambris, Jesus G. Valenzuela and Viviana P. Ferreira J Immunol published online 25 April 2016 http://www.jimmunol.org/content/early/2016/04/23/jimmun ol.1600040 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2016/04/23/jimmunol.160004 Material 0.DCSupplemental http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 29, 2021 *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 © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published April 25, 2016, doi:10.4049/jimmunol.1600040 The Journal of Immunology Properdin-Mediated C5a Production Enhances Stable Binding of Platelets to Granulocytes in Human Whole Blood Adam Z. Blatt,*,1 Gurpanna Saggu,*,1 Koustubh V. Kulkarni,* Claudio Cortes,† Joshua M. Thurman,‡ Daniel Ricklin,x John D. Lambris,x Jesus G. Valenzuela,{ and Viviana P. Ferreira* Enhanced levels of platelet/granulocyte aggregates (PGAs) are found in patients suffering from many different inflammatory vas- cular diseases, and their formation in animal models of vascular disease is associated with increased thromboinflammation and worsened outcomes. The complement system, a part of the innate immune system, influences PGA formation, but the mechanisms for its effects are unknown. In this study, we have defined complement-mediated mechanisms that enhance PGA formation in human whole blood stimulated with thrombin receptor–activating peptide (TRAP) using ex vivo flow cytometry assays. We demonstrate that physiological properdin, a positive regulator of complement alternative pathway activity, increases PGA formation when Downloaded from added to TRAP-stimulated blood. All physiological properdin forms increase PGA formation, but properdin tetramers are the most efficient at increasing complement activity and PGA formation. Inhibition of endogenous properdin, either circulating in the blood or produced locally by leukocytes, impairs TRAP-mediated PGA formation to the same level as specific inhibition of either the alternative or classical pathway. Additionally, blocking the interaction of C5a with its cellular receptor prevents properdin- mediated increases in PGA formation. Adding either properdin tetramers or C5a to whole blood increases CD11b expression on granulocytes, and this increase is prevented by blockade of the C5a–C5a receptor axis. Finally, we demonstrate that the effects of http://www.jimmunol.org/ properdin on PGA formation are tightly regulated by Factor H. Cumulatively, our data indicate that properdin enhances PGA formation via increased production of C5a, and that inhibition of properdin function has therapeutic potential to limit thrombo- inflammation in diseases characterized by increased PGA formation. The Journal of Immunology, 2016, 196: 000–000. latelets are critical for vascular hemostasis and repair in vascular damage (1–4). Leukocytes not only promote inflamma- response to blood vessel damage (1). Platelets also help tion, but they have a dynamic role in the regulation of thrombosis. initiate inflammatory responses that induce endothelial Tissue factor expressed on leukocyte surfaces or leukocyte-derived P by guest on September 29, 2021 regeneration and vessel protection from potential invasion by microparticles increases thrombus formation (5–8), whereas leuko- microorganisms by binding and recruiting leukocytes to sites of cytes limit thrombus formation by directly phagocytosing activated platelets, decreasing local levels of ADP, and preventing fibrinogen binding to platelets (9). Platelets and leukocytes interact to form *Department of Medical Microbiology and Immunology, University of Toledo Col- lege of Medicine and Life Sciences, Toledo, OH 43614; †Department of Biomedical stable platelet/leukocyte aggregates (PLAs) (10), which involves an Sciences, Oakland University William Beaumont School of Medicine, Rochester, MI ordered series of events where P-selectin on activated platelets binds 48309; ‡Department of Medicine, University of Colorado School of Medicine, Au- x to P-selectin glycoprotein ligand-1 (PSGL-1) on leukocytes. This rora, CO 80045; Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; and {Vector Molecular Biology stimulates the upregulation and activation of complement receptor Section, Laboratory of Malaria and Vector Research, National Institute of Allergy 3 (CR3; CD11b/CD18; Mac-1) on leukocytes, which then binds and Infectious Diseases, National Institutes of Health, Rockville, MD 20852 multiple ligands on platelets to form stable aggregates (11–14). 1 A.Z.B. and G.S. contributed equally to this work. Excessive PLA formation increases tissue factor expression, se- ORCIDs: 0000-0003-2870-0028 (C.C.); 0000-0001-6140-0233 (D.R.); 0000-0001- cretion of proinflammatory cytokines and chemokines, produc- 8923-5671 (V.P.F.). tion of reactive oxygen species, secretion of damaging proteases, Received for publication January 7, 2016. Accepted for publication March 28, 2016. and upregulation of adhesion molecules on leukocytes (11–13). This work was supported by National Institutes of Health Grants R01HL112937 (to Increased levels of circulating PLAs are found in patients suf- V.P.F.), R01DK076690 (to J.M.T.), and P01AI068730 (to J.D.L.), as well as by American Heart Association Predoctoral Fellowship 15PRE25230012 (to A.Z.B.). fering from many inflammatory diseases, including cardiovascular, Address correspondence and reprint requests to Dr. Viviana P. Ferreira, Department myeloproliferative, and inflammatory bowel diseases (15–20), and of Medical Microbiology and Immunology, University of Toledo College of Medi- inhibiting PLA formation (by inhibiting P-selectin or CD11b) re- cine and Life Sciences, 3000 Arlington Avenue, Mail Stop 1021, Health Education duces pathology and improves outcomes in various vascular injury Building 259C, Toledo, OH 43614. E-mail address: [email protected] animal models (8, 21–24). Understanding mechanisms by which The online version of this article contains supplemental material. PLA formation is regulated is imperative to elucidate how PLAs Abbreviations used in this article: aHUS, atypical hemolytic uremic syndrome; AP, can increase to levels that result in pathologic thromboinflammation alternative pathway; C5aR1, C5a receptor 1; CP, classical pathway; CR3, comple- ment receptor 3; FH, Factor H; HT, HEPES/Tyrode’s; MAC, membrane attack com- and to identify potential therapeutic targets. plex; NA, nonactivated; NA+Comp, nonactivated plus compstatin; P2, dimeric form The complement system links the innate and adaptive immune of properdin; P3, trimeric form of properdin; P4, tetrameric form of properdin; PGA, systems and helps orchestrate inflammatory reactions. Comple- platelet/granulocyte aggregate; PLA, platelet/leukocyte aggregate; Pn, nonphysiolog- ical aggregated form of properdin; PSGL-1, P-selectin glycoprotein ligand-1; rH19– ment activity can initiate by three distinct pathways (classical, 20, recombinant protein consisting of domains 19–20 of Factor H; TRAP, thrombin lectin, and alternative) that converge at the cleavage of the central receptor–activating peptide. molecule, C3, to C3b and C3a. C3b binds covalently to exposed Copyright Ó 2016 by The American Association of Immunologists, Inc. 0022-1767/16/$30.00 hydroxyl and amino groups on cell surfaces, enabling the formation www.jimmunol.org/cgi/doi/10.4049/jimmunol.1600040 2 ROLE OF PROPERDIN IN PGA FORMATION of C3/C5 convertases that amplify complement activity and lead to Purification of properdin and separation of physiological forms activation of terminal complement components to produce the ana- Purification of properdin from normal human plasma was carried out as phylatoxin C5a and the membrane attack complex (MAC; C5b-9) previously described (30). Physiological polymeric forms of properdin (P2, (25). Although all three pathways recognize distinct molecular P3,P4) were separated from Pns by gel filtration chromatography. Briefly, patterns on cell surfaces to activate, the alternative pathway (AP) pure properdin (5 mg) was loaded onto a Phenomenex BioSep-Sec-S4000 3 3 mainly initiates spontaneously in the fluid phase (25, 26). Pro- column (600 7.8 mm) with a guard column (75 7.8 mm) and eluted at a 0.5 ml/min flow rate in PBS. Purified, physiological forms of properdin perdin, the only known positive complement regulatory molecule, were stored at 4˚C and used within 2 wk of separation (28, 30). stabilizes the AP convertases, increasing their activity 5- to 10-fold (26). The AP amplifies on any surface on
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