The Platelet-Leukocyte Switch in Vascular Disease

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Platelet-leukocyte interactions occupy a central role in the interface between thrombosis and inflammation and may contribute to intimal hyperplasia, atherosclerosis, and microvascular occlusion. We and others have demonstrated that the early recruitment of neutrophils by adherent platelets following arterial endothelial denudation injury correlates with the subsequent development of intimal hyperplasia. The recruitment of leukocytes by platelets may serve as a crucial switch in the injury response that converts the dominant biology to inflammation with leukocyte infiltration into the vessel wall and initiation of a local and systemic inflammatory response. We hypothesize that unique molecular determinants control the binding of neutrophils to platelets and their subsequent transmigration. The broad objective of this application is to define the molecular events that are triggered in neutrophils upon binding to platelets and then target those pathways in mice to delineate their relative contributions to the response to arterial injury and to neutrophil extravasation across inflammed endothelium. We have identified a signaling pathway in neutrophils that is initiated upon contact with P-selectin and appears to activate Rap1 and integrin alphaMbeta2. Src-family kinase (SFK) and Pyk2 serve as sensors of beta2 integrin engagement and stabilize firm integrin adhesion. Our data suggests that Pyk2 activity is regulated by phosphodiesterase-sensitive cAMP pools. In Specific Aim One, we will identify the molecular determinants of Pyk2-dependent signaling and the relative contribution(s) to physiologically relevant platelet-leukocyte interactions. In Specific Aim Two, we will establish a role for Rap1 in promoting platelet-leukocyte interactions and pathophysiologic vascular injury responses. In Specific Aim Three, we will identify unique controls for the platelet-leukocyte switch using animal models of acute inflammation and isolated cell systems. This work will define specific signaling events that are initiated in neutrophils upon adhesion to platelets and their relative contributions to acute inflammatory processes in potentially clinically-relevant models. Successful completion of the work should validate pharmacologic strategies aimed at blocking platelet-neutrophil interactions as a novel approach to treat or prevent atherothrombotic vascular disease.