Platelet CD40L mediates thrombotic and inflammatory processes in atherosclerosis.
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.
Lievens
Dirk
D
Department of Pathology, Maastricht Center for Atherosclerosis Research, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.
Zernecke
Alma
A
Seijkens
Tom
T
Soehnlein
Oliver
O
Beckers
Linda
L
Munnix
Imke C A
IC
Wijnands
Erwin
E
Goossens
Pieter
P
van Kruchten
Roger
R
Thevissen
Larissa
L
Boon
Louis
L
Flavell
Richard A
RA
Noelle
Randolph J
RJ
Gerdes
Norbert
N
Biessen
Erik A
EA
Daemen
Mat J A P
MJ
Heemskerk
Johan W M
JW
Weber
Christian
C
Lutgens
Esther
E
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*
D018932:Chemokine CCL2; D023201:CD40 Ligand; D007501:Iron