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

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 und Lutgens, Esther (2016): Platelet CD40 Exacerbates Atherosclerosis by Transcellular Activation of Endothelial Cells and Leukocytes. In: Arteriosclerosis thrombosis and Vascular Biology, Bd. 36, Nr. 3: S. 482-490

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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1079-5642
• Sprache: Englisch