Abstract 178: Platelet Cd40 Exacerbates Atherosclerosis by Transcellular Activation of Endothelial Cells and Leukocytes

Abstract

Beyond their eminent role in hemostasis and thrombosis, platelets are recognized as mediators of inflammation and protagonists of atherogenesis. Here we investigated the inflammatory propensity of platelet-specific expression of CD40, the most common receptor for CD40L. Besides its presence on immune cells and other cell types, CD40 is constitutively expressed on platelets where its function is largely unknown.

CD40-deficient platelets exhibited impaired thrombin-induced activation, reflected by decreased P-selectin expression and αIIbβ3 integrin activation. Compared to infusion of activated Apoe-/- platelets, injection of activated Cd40-/-Apoe-/- platelets caused a >2-fold decrease in plaque size in the aortic arch (Apoe-/- platelets 18.3x104 ± 2.7x104 μm2 vs Cd40-/-Apoe-/- platelets 6.7 x104 ± 2.1 x104 μm2, Vehicle 9.8 x104 ± 2.8 x104 μm2, p<0.05) of Apoe-/- mice. Intravital microscopy of carotid arteries revealed impaired platelet adhesion and impeded leukocyte recruitment to the arterial wall of mice injected with activated Cd40-/-Apoe-/- platelets, which was accompanied by a decrease in endothelial VCAM-1 expression. Moreover, Cd40-/-Apoe-/- platelets displayed a reduced capacity to form platelet-leukocyte aggregates in vitro with these co-incubations releasing less IL-1β. Interestingly, once a thrombus had formed, leukocyte recruitment into thrombi was hampered in Cd40-/-Apoe-/- thrombi.

This study ascribes an essential function to platelet CD40 in atherosclerosis. Besides platelet activation, platelet CD40 induces activation of leukocytes and endothelial cells, thereby promoting inflammation and consequently atherogenesis.