In the U.S., cardiovascular disease is the leading cause of mortality in men and women. Patients with inflammatory cardiovascular disease have an increased number of circulating activated platelets and platelet/leukocyte aggregates, both of which play a central role in the initiation and progression of disease. Activated platelets promote the initiation and propagation of the complement system on their surface, leading to vascular inflammation and thrombosis. We have recently reported a molecular mechanism by which properdin, a positive regulator of the alternative pathway of complement, binds directly to activated, but not to resting platelets, independently from C3b, and initiates complement activation. Our novel preliminary data demonstrate ex-vivo that human properdin increases platelet/leukocyte aggregate formation and the development of collagen-induced thrombi in whole blood subjected to shear stress. Inhibition of properdin binding to C3b and to cells significantly reduces both outcomes. The mechanisms underlying how properdin stimulates the interaction between platelets and leukocytes are unknown and the objective of this proposal is to define these mechanisms. Properdin is produced mainly by activated leukocytes. In inflammatory microenvironments, activated leukocytes and platelets directly interact with one another, and the leukocyte- derived properdin would be available to platelets at high concentrations. We hypothesize that properdin enhances the interaction between platelets and leukocytes via complement alternative pathway-dependent mechanisms including, at least in part, properdin-initiated complement activation, as well as via mechanisms that do not depend on complement activation (i.e. serving as a bridge between cells). To address this hypothesis we propose the following aims: (1) To determine how the interaction of properdin with C3b as well as with platelets and leukocytes can be inhibited in order to prevent, on these cells, properdin-mediated stabilization of convertases or properdin-initiated complement activation, and/or complement-independent properdin effects; (2) To characterize the contribution of properdin and of the alternative pathway to the interaction between platelets and leukocytes by using pathway- and effector-specific complement inhibitors in ex-vivo analyses of platelet/leukocyte aggregate and thrombi formation in human whole blood. Collectively, these studies will significantly advance the understanding of the functions of human properdin and the alternative pathway in the pathogenesis of vascular diseases by defining a new molecular mechanism for platelet/leukocyte interactions. In addition, by identifying candidate inhibitors of properdin functions, this study will allow the design of unique therapeutic strategies to modulate the interaction between platelet and leukocytes for treating cardiovascular diseases where complement, platelet/leukocyte aggregates, and thrombi play key roles in the pathogenesis.
Cardiovascular disease is the leading cause of mortality in many countries. We are investigating a novel mechanism whereby complement protein properdin binds to blood platelets and neutrophils and enhances their interaction, promoting the aggregation of these cells in blood as well as formation of thrombi. Understanding how this cellular interaction is promoted and how it can be inhibited will lead us to new treatments for important cardiovascular diseases.
| Chen, Jin Y; Cortes, Claudio; Ferreira, Viviana P (2018) Properdin: A multifaceted molecule involved in inflammation and diseases. Mol Immunol 102:58-72 |
| Blatt, Adam Z; Saggu, Gurpanna; Cortes, Claudio et al. (2017) Factor H C-Terminal Domains Are Critical for Regulation of Platelet/Granulocyte Aggregate Formation. Front Immunol 8:1586 |
| Blatt, Adam Z; Pathan, Sabina; Ferreira, Viviana P (2016) Properdin: a tightly regulated critical inflammatory modulator. Immunol Rev 274:172-190 |
| Sherpa, Rinzhin T; Atkinson, Kimberly F; Ferreira, Viviana P et al. (2016) RAPAMYCIN INCREASES LENGTH AND MECHANOSENSORY FUNCTION OF PRIMARY CILIA IN RENAL EPITHELIAL AND VASCULAR ENDOTHELIAL CELLS. Int Educ Res J 2:91-97 |
| Blatt, Adam Z; Saggu, Gurpanna; Kulkarni, Koustubh V et al. (2016) Properdin-Mediated C5a Production Enhances Stable Binding of Platelets to Granulocytes in Human Whole Blood. J Immunol 196:4671-4680 |
