Platelet CD40L mediates thrombotic and inflammatory processes in atherosclerosis

Dirk Lievens, Alma Zernecke, Tom Seijkens, Oliver Soehnlein, Linda Beckers, Imke C. A. Munnix, Erwin Wijnands, Pieter Goossens, Roger van Kruchten, Larissa Thevissen, Louis Boon, Richard A. Flavell, Randolph J. Noelle, Norbert Gerdes, Erik A. Biessen, Mat J.A.P. Daemen, JohanW. M. Heemskerk, Christian Weber, Esther Lutgens*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

201 Citations (Web of Science)

Abstract

CD40 ligand (CD40L), identified as a costimulatory molecule expressed on T cells, is also expressed and functional on platelets. We investigated the thrombotic and inflammatory contributions of platelet CD40L in atherosclerosis. Although CD40L-deficient (Cd40l(-/-))platelets exhibited impaired platelet aggregation and thrombus stability, the effects of platelet CD40L on inflammatory processes in atherosclerosis were more remarkable. Repeated injections of activated Cd40l(-/-) platelets into Apoe(-/-) mice strongly de-creased both platelet and leukocyte adhesion to the endothelium and decreased plasma CCL2 levels compared with wildtype platelets. Moreover, Cd40l(-/-) platelets failed to form proinflammatory platelet-leukocyte aggregates. Expression of CD40L on platelets was required for plateletinduced atherosclerosis as injection of Cd40l(-/-) platelets in contrast to Cd40l(-/-) platelets did not promote lesion formation. Remarkably, injection of Cd40l(-/-), but not Cd40l(-/-), platelets transiently decreased the amount of regulatory T cells (Tregs) in blood and spleen. Depletion of Tregs in mice injected with activated Cd40l(-/-) platelets abrogated the athero-protective effect, indicating that CD40L on platelets mediates the reduction of Tregs leading to accelerated atherosclerosis. We conclude that platelet CD40L plays a pivotal role in atherosclerosis, not only by affecting platelet-platelet interactions but especially by activating leukocytes, thereby increasing platelet-leukocyte and leukocyte-endothelium interactions. (Blood. 2010;116(20):4317-4327)
Original languageEnglish
Pages (from-to)4317-4327
JournalBlood
Volume116
Issue number20
DOIs
Publication statusPublished - 18 Nov 2010

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