Platelet CD40 Exacerbates Atherosclerosis by Transcellular Activation of Endothelial Cells and Leukocytes

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 36; no. 3; pp. 482 - 490
• Main 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
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 01.03.2016
• Subjects: Animals; Apolipoproteins E - deficiency; Apolipoproteins E - genetics; Atherosclerosis - blood; Atherosclerosis - genetics; Atherosclerosis - pathology; Atherosclerosis - prevention & control; Blood Platelets - metabolism; CD40 Antigens - blood; CD40 Antigens - deficiency; CD40 Antigens - genetics; CD40 Ligand - blood; Cells, Cultured; Chemotaxis; Coculture Techniques; Diet, High-Fat; Disease Models, Animal; Endothelial Cells - metabolism; Humans; Inflammation - blood; Inflammation - genetics; Inflammation - pathology; Inflammation - prevention & control; Leukocytes - metabolism; Male; Mice, Inbred C57BL; Mice, Knockout; P-Selectin - blood; P-Selectin - genetics; Plaque, Atherosclerotic; Platelet Adhesiveness; Platelet Aggregation; Platelet Transfusion; Signal Transduction; Time Factors; atherosclerosis; immune system; leukocytes; blood platelets; CD40 ligand
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/ATVBAHA.115.307074

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 Cd40Apoe 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 Cd40Apoe 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 Cd40Apoe 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.