Platelet CD40L mediates thrombotic and inflammatory processes in atherosclerosis

Dirk Lievens; Alma Zernecke; Tom Seijkens; Oliver Soehnlein; Linda Beckers; Imke C. A. Munnix; Erwin Wijnands; Pieter Goossens; Roger van Kruchten; Larissa Thevissen; Louis Boon; Richard A. Flavell; Randolph J. Noelle; Norbert Gerdes; Erik A. Biessen; Mat J.A.P. Daemen; JohanW. M. Heemskerk; Christian Weber; Esther Lutgens

doi:10.1182/blood-2010-01-261206

Platelet CD40L mediates thrombotic and inflammatory processes in atherosclerosis

Dirk Lievens, Alma Zernecke, Tom Seijkens, Oliver Soehnlein, Linda Beckers, Imke C. A. Munnix, Erwin Wijnands, Pieter Goossens, Roger van Kruchten, Larissa Thevissen, Louis Boon, Richard A. Flavell, Randolph J. Noelle, Norbert Gerdes, Erik A. Biessen, Mat J.A.P. Daemen, JohanW. M. Heemskerk, Christian Weber, Esther Lutgens^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

201 Citations (Web of Science)

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 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)

Original language	English
Pages (from-to)	4317-4327
Journal	Blood
Volume	116
Issue number	20
DOIs	https://doi.org/10.1182/blood-2010-01-261206
Publication status	Published - 18 Nov 2010

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10.1182/blood-2010-01-261206

Cite this

Lievens, D., Zernecke, A., Seijkens, T., Soehnlein, O., Beckers, L., Munnix, I. C. A., Wijnands, E., Goossens, P., van Kruchten, R., Thevissen, L., Boon, L., Flavell, R. A., Noelle, R. J., Gerdes, N., Biessen, E. A., Daemen, M. J. A. P., Heemskerk, J. M., Weber, C., & Lutgens, E. (2010). Platelet CD40L mediates thrombotic and inflammatory processes in atherosclerosis. Blood, 116(20), 4317-4327. https://doi.org/10.1182/blood-2010-01-261206

@article{5ecd4a9659b4478d91491031b9f1a598,

title = "Platelet CD40L mediates thrombotic and inflammatory processes in atherosclerosis",

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 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)",

author = "Dirk Lievens and Alma Zernecke and Tom Seijkens and Oliver Soehnlein and Linda Beckers and Munnix, {Imke C. A.} and Erwin Wijnands and Pieter Goossens and {van Kruchten}, Roger and Larissa Thevissen and Louis Boon and Flavell, {Richard A.} and Noelle, {Randolph J.} and Norbert Gerdes and Biessen, {Erik A.} and Daemen, {Mat J.A.P.} and Heemskerk, {JohanW. M.} and Christian Weber and Esther Lutgens",

year = "2010",

month = nov,

day = "18",

doi = "10.1182/blood-2010-01-261206",

language = "English",

volume = "116",

pages = "4317--4327",

journal = "Blood",

issn = "0006-4971",

publisher = "The American Society of Hematology",

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Lievens, D, Zernecke, A, Seijkens, T, Soehnlein, O, Beckers, L, Munnix, ICA, Wijnands, E, Goossens, P, van Kruchten, R, Thevissen, L, Boon, L, Flavell, RA, Noelle, RJ, Gerdes, N, Biessen, EA, Daemen, MJAP, Heemskerk, JM, Weber, C & Lutgens, E 2010, 'Platelet CD40L mediates thrombotic and inflammatory processes in atherosclerosis', Blood, vol. 116, no. 20, pp. 4317-4327. https://doi.org/10.1182/blood-2010-01-261206

TY - JOUR

T1 - Platelet CD40L mediates thrombotic and inflammatory processes in atherosclerosis

AU - Lievens, Dirk

AU - Zernecke, Alma

AU - Seijkens, Tom

AU - Soehnlein, Oliver

AU - Beckers, Linda

AU - Munnix, Imke C. A.

AU - Wijnands, Erwin

AU - Goossens, Pieter

AU - van Kruchten, Roger

AU - Thevissen, Larissa

AU - Boon, Louis

AU - Flavell, Richard A.

AU - Noelle, Randolph J.

AU - Gerdes, Norbert

AU - Biessen, Erik A.

AU - Daemen, Mat J.A.P.

AU - Heemskerk, JohanW. M.

AU - Weber, Christian

AU - Lutgens, Esther

PY - 2010/11/18

Y1 - 2010/11/18

N2 - 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)

AB - 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)

U2 - 10.1182/blood-2010-01-261206

DO - 10.1182/blood-2010-01-261206

M3 - Article

C2 - 20705757

VL - 116

SP - 4317

EP - 4327

JO - Blood

JF - Blood

SN - 0006-4971

IS - 20

ER -