Platelet-leukocyte interactions in cardiovascular disease and beyond

Abstract

Platelet-leukocyte interactions define a basic cell process that is characterized by the exchange of signals between platelets and different types of leukocytes and that bridges 2 fundamental pathophysiological events: atherothrombosis and inflammatory immune reactions. When this process takes place at the site of atherosclerotic plaque development or at the site of endothelial injury, platelet-dependent leukocyte recruitment and activation contributes to the inflammatory reaction of the vessel wall, which accounts for the exacerbation of atherosclerosis and for intimal hyperplasia and plaque instability. Moreover, platelet-leukocyte interactions may have a key role in modulating a wide array of responses of both the innate and adaptive immune systems, thus contributing to the pathogenesis of inflammatory diseases and tissue damage, as well as to host defense.

Figure 1. Molecular pathways of platelet–leukocyte communication

Recognition is the first step of platelet–leukocyte adhesion, and it is mainly mediated through the binding of P-selectin to PSGL-1. The rapid response follows signals transduced by the adhesive receptors (initially by PSGL-1, and subsequently by the engaged β2 integrins) and by platelet-derived CC and CXC chemokine receptors. These are seven-transmembrane-domain receptors that are coupled to G-proteins and initiate signal transduction, to trigger a multitude of cellular responses. Together, these signals induce immediate responses in leukocytes in particular: full integrin activation and firm adhesion, chemotaxis and transmigration, release of granule contents, and ROS production. The delayed response is regulated by the concerted action of outside-in signaling, which is transmitted by adhesive receptors (mainly PSGL-1 and β2-integrins) and signals transmitted by receptors for chemokines and cytokines that are presented on the platelet surface or that are released as soluble molecules by activated platelets. These signals induce the nuclear translocation of the transcription factor NF-kB which mediates expression of the inflammatory phenotype.

Figure 2. Contribution of platelet–leukocyte interactions to inflammatory-immune responses

Platelets are activated at the site of endothelial damage or in the microcirculation of infected/inflamed tissue. Activated platelets bind leukocytes to form heterotypic complexes, and communicate signals that result in a variety of specific responses. Platelets mediate the recruitment of leukocytes at the site of atherosclerosis or thrombus formation, as well as in inflamed tissue. In some cases, these interactions mediate platelet–leukocyte co-migration across the mucosal epithelium. In this way, platelets contribute to the promotion of inflammatory reactions, which when not controlled, can exacerbate tissue damage. Platelet might support lymphocyte homing in peripheral lymph nodes, stimulate isotype switching and production of IgG by B lymphocytes, and might help lymphocyte responses to viruses and neutrophil response to bacteria. In this way, platelets contribute to host defense.