期刊
BLOOD
卷 116, 期 20, 页码 4317-4327出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2010-01-261206
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资金
- Humboldt Foundation
- Netherlands Organization for Scientific Research
- Netherlands Heart Foundation
- German Research Foundation DFG [FOR809, WE1913/7-2, 10-1, ZE827/1-1]
- Interdisciplinary Center for Clinical Research BIOMAT within the Faculty of Medicine at the Rheinisch-Westfalische Technische Hochschule Aachen University
- Medical Research Council [G0802651, G0600698B] Funding Source: researchfish
- MRC [G0802651] Funding Source: UKRI
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)
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