Platelet CD40L mediates thrombotic and inflammatory processes in atherosclerosis.

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.

[1]  Oliver Soehnlein,et al.  Deficient CD40-TRAF6 signaling in leukocytes prevents atherosclerosis by skewing the immune response toward an antiinflammatory profile , 2010, The Journal of experimental medicine.

[2]  G. Stoll,et al.  Impaired αIIbβ3 Integrin Activation and Shear-Dependent Thrombus Formation in Mice Lacking Phospholipase D1 , 2010, Science Signaling.

[3]  K. Ley,et al.  Immune and inflammatory mechanisms of atherosclerosis (*). , 2009, Annual review of immunology.

[4]  P. Hordijk,et al.  Molecular and functional interactions among monocytes, platelets, and endothelial cells and their relevance for cardiovascular diseases , 2009, Journal of leukocyte biology.

[5]  A. Zernecke,et al.  Disrupting functional interactions between platelet chemokines inhibits atherosclerosis in hyperlipidemic mice , 2009, Nature Medicine.

[6]  C. Gleissner,et al.  Platelet Chemokines in Vascular Disease , 2008, Arteriosclerosis, thrombosis, and vascular biology.

[7]  P. Libby,et al.  The multifaceted contributions of leukocyte subsets to atherosclerosis: lessons from mouse models , 2008, Nature Reviews Immunology.

[8]  P. Hordijk,et al.  Transendothelial migration drives dissociation of plateletmonocyte complexes , 2008, Thrombosis and Haemostasis.

[9]  L. Beckers,et al.  The CD40-TRAF6 axis is the key regulator of the CD40/CD40L system in neointima formation and arterial remodeling. , 2008, Blood.

[10]  P. Carmeliet,et al.  Gas6 promotes inflammation by enhancing interactions between endothelial cells, platelets, and leukocytes. , 2008, Blood.

[11]  Guohong Li,et al.  Copyright © American Society for Investigative Pathology DOI: 10.2353/ajpath.2008.070633 Vascular Biology, Atherosclerosis and Endothelium Biology CD40 Ligand Promotes Mac-1 Expression, Leukocyte Recruitment, and Neointima Formation after Vascular Injury , 2022 .

[12]  M. Gawaz,et al.  Platelets: Inflammatory Firebugs of Vascular Walls , 2008, Arteriosclerosis, thrombosis, and vascular biology.

[13]  M. Gawaz,et al.  Platelet-vessel Wall Interactions in Atherosclerotic Disease Theme Issue Article Platelet Secretion Andgeneration of Cytokines , 2022 .

[14]  M. J.,et al.  Transendothelial migration drives dissociation of platelet-monocyte complexes , 2008 .

[15]  J. Bernhagen,et al.  MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment , 2007, Nature Medicine.

[16]  G. Lippi,et al.  Risk stratification of patients with acute myocardial infarction by quantification of circulating monocyte-platelet aggregates. , 2007, International journal of cardiology.

[17]  C. Weber,et al.  Platelets as Immune Cells: Bridging Inflammation and Cardiovascular Disease , 2007, Circulation research.

[18]  R. Flavell,et al.  Natural regulatory T cells control the development of atherosclerosis in mice , 2006, Nature Medicine.

[19]  Elisabetta Dejana,et al.  Importance of junctional adhesion molecule-A for neointimal lesion formation and infiltration in atherosclerosis-prone mice. , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[20]  M. Gawaz,et al.  Platelets in inflammation and atherogenesis. , 2005, The Journal of clinical investigation.

[21]  M. V. van Zandvoort,et al.  The Glycoprotein VI-Phospholipase C&ggr;2 Signaling Pathway Controls Thrombus Formation Induced by Collagen and Tissue Factor In Vitro and In Vivo , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[22]  J. Freedman,et al.  CD40 Ligand Influences Platelet Release of Reactive Oxygen Intermediates , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[23]  C. Mackay,et al.  Gene Profiling in Atherosclerosis Reveals a Key Role for Small Inducible Cytokines: Validation Using a Novel Monocyte Chemoattractant Protein Monoclonal Antibody , 2005, Circulation.

[24]  C. Weber.  Platelets and chemokines in atherosclerosis: partners in crime. , 2005, Circulation research.

[25]  Christian Weber,et al.  Heterophilic interactions of platelet factor 4 and RANTES promote monocyte arrest on endothelium. , 2005, Blood.

[26]  A. Graybiel,et al.  CalDAG-GEFI integrates signaling for platelet aggregation and thrombus formation , 2004, Nature Medicine.

[27]  W. Ouwehand,et al.  Platelet receptor interplay regulates collagen-induced thrombus formation in flowing human blood. , 2004, Blood.

[28]  P. Hordijk,et al.  Platelet-Monocyte Complexes Support Monocyte Adhesion to Endothelium by Enhancing Secondary Tethering and Cluster Formation , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[29]  K. Ley,et al.  Role of platelets in the development of atherosclerosis. , 2004, Trends in cardiovascular medicine.

[30]  Georg Kraal,et al.  Inhibition of NF-kappaB activation in macrophages increases atherosclerosis in LDL receptor-deficient mice. , 2003, The Journal of clinical investigation.

[31]  M. Gawaz,et al.  Activated platelets trigger an inflammatory response and enhance migration of aortic smooth muscle cells. , 2003, Thrombosis research.

[32]  B. Nieswandt,et al.  Complementary roles of platelet glycoprotein VI and integrin α2β1 in collagen‐induced thrombus formation in flowing whole blood ex vivo , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[33]  Andreas Schober,et al.  Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein E , 2003, Nature Medicine.

[34]  M. Gawaz,et al.  A Critical Role of Platelet Adhesion in the Initiation of Atherosclerotic Lesion Formation , 2002, The Journal of experimental medicine.

[35]  Patrick André,et al.  Platelet-derived CD40L: the switch-hitting player of cardiovascular disease. , 2002, Circulation.

[36]  J. Vermylen,et al.  atherosclerosis-prone sites in response to hypercholesterolemia Endothelial von Willebrand factor recruits platelets to , 2013 .

[37]  R. Hynes,et al.  CD40L stabilizes arterial thrombi by a β3 integrin–dependent mechanism , 2002, Nature Medicine.

[38]  P. Libby,et al.  CD40 Signaling and Plaque Instability , 2001, Circulation research.

[39]  R. Goldberg,et al.  Circulating monocyte-platelet aggregates are an early marker of acute myocardial infarction. , 2001, Journal of the American College of Cardiology.

[40]  K. Ley,et al.  RANTES Deposition by Platelets Triggers Monocyte Arrest on Inflamed and Atherosclerotic Endothelium , 2001, Circulation.

[41]  T. V. van Berkel,et al.  Induction of Rapid Atherogenesis by Perivascular Carotid Collar Placement in Apolipoprotein E–Deficient and Low-Density Lipoprotein Receptor–Deficient Mice , 2001, Circulation.

[42]  P. Libby,et al.  The CD40/CD154 receptor/ligand dyadRID="†"ID="†" Review , 2001, Cellular and Molecular Life Sciences CMLS.

[43]  Xinghua Zhou,et al.  Transfer of CD4+ T Cells Aggravates Atherosclerosis in Immunodeficient Apolipoprotein E Knockout Mice , 2000, Circulation.

[44]  R. Callard,et al.  Biological function of CD40 on human endothelial cells: costimulation with CD40 ligand and interleukin‐4 selectively induces expression of vascular cell adhesion molecule‐1 and P‐selectin resulting in preferential adhesion of lymphocytes , 2000, Immunology.

[45]  M. Daemen,et al.  Both early and delayed anti-CD40L antibody treatment induces a stable plaque phenotype. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[46]  P. Libby,et al.  Inhibition of CD40 signaling limits evolution of established atherosclerosis in mice. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[47]  R. Virmani,et al.  Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. , 2000, Arteriosclerosis, thrombosis, and vascular biology.

[48]  M. Daemen,et al.  Requirement for CD154 in the progression of atherosclerosis , 1999, Nature Medicine.

[49]  I. Charo,et al.  Decreased lesion formation in CCR2−/− mice reveals a role for chemokines in the initiation of atherosclerosis , 1998, Nature.

[50]  P. Libby,et al.  Reduction of atherosclerosis in mice by inhibition of CD40 signalling , 1998, Nature.

[51]  M. Yellin,et al.  CD40L‐CD40 interactions regulate endothelial cell surface tissue factor and thrombomodulin expression , 1998, Journal of leukocyte biology.

[52]  Reinhold Förster,et al.  CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells , 1998, Nature.

[53]  R. Becker,et al.  Increased platelet reactivity and circulating monocyte-platelet aggregates in patients with stable coronary artery disease. , 1998, Journal of the American College of Cardiology.

[54]  J. Heemskerk,et al.  Collagen but not fibrinogen surfaces induce bleb formation, exposure of phosphatidylserine, and procoagulant activity of adherent platelets: evidence for regulation by protein tyrosine kinase-dependent Ca2+ responses. , 1997, Blood.

[55]  M. Feldmann,et al.  Platelet-derived interleukin 1 induces human endothelial adhesion molecule expression and cytokine production , 1991, The Journal of experimental medicine.

[56]  B. Smith,et al.  Dynamics of leukocyte-platelet adhesion in whole blood. , 1991, Blood.

[57]  L Roy,et al.  Platelet activation in unstable coronary disease. , 1986, The New England journal of medicine.