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

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
Number of pages	11
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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https://www.ncbi.nlm.nih.gov/pmc/articles/2993630Licence: Other

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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 = "Elsevier B.V.",

number = "20",

}

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

SN - 0006-4971

VL - 116

SP - 4317

EP - 4327

JO - Blood

JF - Blood

IS - 20

ER -

Platelet CD40L mediates thrombotic and inflammatory processes in atherosclerosis

Abstract

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