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Platelet CD40L mediates thrombotic and inflammatory processes in atherosclerosis.

Authors: Lievens, D  Zernecke, A  Seijkens, T  Soehnlein, O  Beckers, L  Munnix, IC  Wijnands, E  Goossens, P  Van Kruchten, R  Thevissen, L  Boon, L  Flavell, RA  Noelle, RJ  Gerdes, N  Biessen, EA  Daemen, MJ  Heemskerk, JW  Weber, C  Lutgens, E 
Citation: Lievens D, etal., Blood. 2010 Nov 18;116(20):4317-27. Epub 2010 Aug 12.
Pubmed: (View Article at PubMed) PMID:20705757
DOI: Full-text: DOI:10.1182/blood-2010-01-261206

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.


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RGD Object Information
RGD ID: 5490529
Created: 2011-09-15
Species: All species
Last Modified: 2011-09-15
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.