Department of Pathology, Maastricht Center for Atherosclerosis Research, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.
Blood. 2010 Nov 18;116(20):4317-27. doi: 10.1182/blood-2010-01-261206. Epub 2010 Aug 12.
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.
CD40 配体（CD40L）被鉴定为 T 细胞上表达的一种共刺激分子，也在血小板上表达和发挥功能。我们研究了血小板 CD40L 在动脉粥样硬化中的血栓形成和炎症作用。尽管 CD40L 缺陷型（Cd40l(-/-)）血小板表现出血小板聚集和血栓稳定性受损，但血小板 CD40L 对动脉粥样硬化中炎症过程的影响更为显著。反复向 Apoe(-/-) 小鼠注射激活的 Cd40l(-/-)血小板强烈降低了血小板和白细胞与内皮的黏附，并降低了血浆 CCL2 水平，与野生型血小板相比。此外，Cd40l(-/-)血小板未能形成促炎血小板-白细胞聚集物。血小板 CD40L 的表达是血小板诱导动脉粥样硬化所必需的，因为与 Cd40l(+/+)血小板相比，注射 Cd40l(-/-)血小板不会促进病变形成。值得注意的是，与 Cd40l(+/+)血小板相比，注射 Cd40l(-/-)血小板会暂时减少血液和脾脏中调节性 T 细胞（Tregs）的数量。在注射激活的 Cd40l(-/-)血小板的小鼠中耗尽 Tregs 会消除动脉粥样硬化的保护作用，表明血小板上的 CD40L 通过减少 Tregs 介导，从而导致动脉粥样硬化加速。我们得出结论，血小板 CD40L 在动脉粥样硬化中起着关键作用，不仅通过影响血小板-血小板相互作用，而且特别通过激活白细胞，从而增加血小板-白细胞和白细胞-内皮相互作用。
