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 wildtype platelets. Moreover, Cd40l-/- platelets failed to form proinflammatory plateletleukocyte 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.
Original language | English (US) |
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Pages (from-to) | 4317-4327 |
Number of pages | 11 |
Journal | Blood |
Volume | 116 |
Issue number | 20 |
DOIs | |
State | Published - Nov 18 2010 |
ASJC Scopus subject areas
- Biochemistry
- Immunology
- Hematology
- Cell Biology