Platelet CD40L mediates thrombotic and inflammatory processes in atherosclerosis

被引：239

作者：

Lievens, Dirk ^{[1
,2
]}

Zernecke, Alma ^{[2
]}

Seijkens, Tom ^{[1
]}

Soehnlein, Oliver ^{[2
]}

Beckers, Linda ^{[1
]}

Munnix, Imke C. A. ^{[3
]}

Wijnands, Erwin ^{[1
]}

Goossens, Pieter ^{[4
]}

van Kruchten, Roger ^{[3
]}

Thevissen, Larissa ^{[2
]}

Boon, Louis ^{[5
]}

Flavell, Richard A. ^{[6
,7
]}

Noelle, Randolph J. ^{[8
,9
,10
]}

Gerdes, Norbert ^{[2
]}

Biessen, Erik A. ^{[1
]}

Daemen, Mat J. A. P. ^{[1
]}

Heemskerk, JohanW. M. ^{[3
]}

Weber, Christian ^{[1
,2
]}

Lutgens, Esther ^{[1
,2
]}

机构：

[1] Univ Maastricht, Dept Pathol, Cardiovasc Res Inst Maastricht, Maastricht Ctr Atherosclerosis Res, NL-6229 HX Maastricht, Netherlands

[2] Rhein Westfal Tech Hsch Aachen Univ, Inst Mol Cardiovasc Res, Aachen, Germany

[3] Univ Maastricht, Dept Biochem, Cardiovasc Res Inst Maastricht, Maastricht Ctr Atherosclerosis Res, NL-6229 HX Maastricht, Netherlands

[4] Univ Maastricht, Dept Mol Genet, Cardiovasc Res Inst Maastricht, Maastricht Ctr Atherosclerosis Res, NL-6229 HX Maastricht, Netherlands

[5] Bioceros BV, Utrecht, Netherlands

[6] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT USA

[7] Yale Univ, Howard Hughes Med Inst, Sch Med, New Haven, CT 06511 USA

[8] Dartmouth Med Sch, Dept Microbiol & Immunol, Lebanon, NH USA

[9] Norris Cotton Canc Ctr, Lebanon, NH USA

[10] Kings Coll London, MRC, Ctr Transplantat, London WC2R 2LS, England

来源：

BLOOD | 2010年 / 116卷 / 20期

关键词：

RECEPTOR-DEFICIENT MICE; ENDOTHELIAL-CELLS; APOLIPOPROTEIN-E; LESION FORMATION; FUNCTIONAL INTERACTIONS; CARDIOVASCULAR-DISEASE; NEOINTIMA FORMATION; MONOCYTE COMPLEXES; GLYCOPROTEIN-VI; TISSUE FACTOR;

D O I：

10.1182/blood-2010-01-261206

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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)

引用

页码：4317 / 4327

页数：11

共 56 条

[1] Natural regulatory T cells control the development of atherosclerosis in mice [J].