title: Platelet CD40L mediates thrombotic and inflammatory processes in atherosclerosis.
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 decreased both platelet and leukocyte adhesion to the endothelium and decreased plasma CCL2 levels compared with wild-type platelets. Moreover, Cd40l(-/-) platelets failed to form proinflammatory platelet-leukocyte aggregates. Expression of CD40L on platelets was required for platelet-induced 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.
authors: Department of Pathology, Maastricht Center for Atherosclerosis Research, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.
authors: Dirk
authors: D
authors: Lievens
authors: Alma
authors: A
authors: Zernecke
authors: Tom
authors: T
authors: Seijkens
authors: Oliver
authors: O
authors: Soehnlein
authors: Linda
authors: L
authors: Beckers
authors: Imke C A
authors: IC
authors: Munnix
authors: Erwin
authors: E
authors: Wijnands
authors: Pieter
authors: P
authors: Goossens
authors: Roger
authors: R
authors: van Kruchten
authors: Larissa
authors: L
authors: Thevissen
authors: Louis
authors: L
authors: Boon
authors: Richard A
authors: RA
authors: Flavell
authors: Randolph J
authors: RJ
authors: Noelle
authors: Norbert
authors: N
authors: Gerdes
authors: Erik A
authors: EA
authors: Biessen
authors: Mat J A P
authors: MJ
authors: Daemen
authors: Johan W M
authors: JW
authors: Heemskerk
authors: Christian
authors: C
authors: Weber
authors: Esther
authors: E
authors: Lutgens
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D001792:Blood Platelets / Q000378:metabolism*; D023201:CD40 Ligand / Q000378:metabolism*; D002450:Cell Communication; D002465:Cell Movement; D018932:Chemokine CCL2 / Q000378:metabolism; D018450:Disease Progression; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D006706:Homeostasis; D007249:Inflammation / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D007501:Iron / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D010641:Phenotype; D013601:T-Lymphocytes / Q000276:immunology; D013927:Thrombosis / Q000150:complications / Q000378:metabolism* / Q000473:pathology*
chemical_list: D018932:Chemokine CCL2; D023201:CD40 Ligand; D007501:Iron