Platelet CD40 Exacerbates Atherosclerosis by Transcellular Activation of Endothelial Cells and Leukocytes. Issue 3 (March 2016)

• Record Type: Journal Article
• Authors: Gerdes, Norbert; Seijkens, Tom; Lievens, Dirk; Kuijpers, Marijke J.E.; Winkels, Holger; Projahn, Delia; Hartwig, Helene; Beckers, Linda; Megens, Remco T.A.; Boon, Louis; Noelle, Randolph J.; Soehnlein, Oliver; Heemskerk, Johan W.M.; Weber, Christian; Lutgens, Esther
• Is Part Of: Arteriosclerosis, thrombosis, and vascular biology. Volume 36:Issue 3(2016)
• Publication Date: 2016-03
• Subjects: atherosclerosis -- blood platelets -- CD40 ligand -- immune system -- leukocytes; Arteriosclerosis -- Periodicals; Thrombosis -- Periodicals; Blood-vessels -- Pathophysiology -- Periodicals; Electronic journals; 616.13
• DOI: 10.1161/ATVBAHA.115.307074
• Languages: English
• ISSNs: 1079-5642

Abstract

Abstract : Objective—: Beyond their eminent role in hemostasis and thrombosis, platelets are recognized as mediators of inflammation. Platelet cluster of differentiation 40 (CD40) ligand (CD40L and CD154) plays a key role in mediating platelet-induced inflammation in atherosclerosis. CD40, the receptor for CD40L, is present on platelets; however, the role of CD40 on this cell type is until now undefined. Approach and Results—: We found that in both mice and humans, platelet CD40 mediates the formation of platelet–leukocyte aggregates and the release of chemokine (C-X-C motif) ligand 4. Leukocytes were also less prone to adhere to CD40-deficient thrombi. However, platelet CD40 was not involved in platelet aggregation. Activated platelets isolated from Cd40 −/− Apoe −/− mice adhered less to the endothelium upon injection into Apoe −/− mice when compared with CD40-sufficient platelets. Furthermore, lack of CD40 on injected platelets led to reduced leukocyte recruitment to the carotid artery as assayed by intravital microscopy. This was accompanied by a decrease in endothelial vascular cell adhesion molecule-1, platelet endothelial cell adhesion molecule, VE-cadherin, and P-selectin expression. To investigate the effect of platelet CD40 in atherosclerosis, Apoe −/− mice received thrombin-activated Apoe −/− or Cd40 −/− Apoe −/− platelets every 5 days for 12 weeks, starting at the age of 17 weeks, when atherosclerotic plaques had already formed. When compared with mice that received Apoe −/− platelets, those receiving Cd40 −/− Apoe −/− platelets exhibited a >2-fold reduction in atherosclerosis. Plaques of mice receiving CD40-deficient platelets were less advanced, contained less macrophages, neutrophils, and collagen, and displayed smaller lipid cores. Conclusions—: Platelet CD40 plays a crucial role in inflammation by stimulating leukocyte activation and recruitment and activation of endothelial cells, thereby promoting atherosclerosis. Abstract : Supplemental Digital Content is available in the text.