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Enzymatic lipid oxidation by eosinophils propagates coagulation, hemostasis and thrombotic disease

Uderhardt, Stefan, Ackermann, Jochen, Fillep, Tobias, Hammond, Victoria J., Willeit, Johann, Santer, Peter, Mayr, Manuel, Biburger, Markus, Miller, Meike, Zellner, Katie R., Stark, Konstantin, Zarbock, Alexander, Rossaint, Jan, Schubert, Irene, Mielenz, Dirk, Diete, Barbara, Raaz-Schrauder, Dorette, Ay, Cihan, Gremmel, Thomas, Thaler, Johannes, Heim, Christian, Herrmann, Martin, Collins, Peter W., Schabbauer, Gernot, Mackman, Nigel, Voehringer, David, Nadler, Jerry L., Lee, James J., Massberg, Steffen, Rauh, Manfred, Kiechl, Stefan, Schett, Georg, O'Donnell, Valerie Bridget and Krönke, Gerhard 2017. Enzymatic lipid oxidation by eosinophils propagates coagulation, hemostasis and thrombotic disease. Journal of Experimental Medicine 214 (7) , pp. 2121-2138. 10.1084/jem.20161070

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Abstract

Blood coagulation is essential for physiological hemostasis, but simultaneously contributes to thrombotic disease. However, molecular and cellular events controlling initiation and propagation of coagulation are still incompletely understood. Here we demonstrate an unexpected role of eosinophils during plasmatic coagulation, hemostasis and thrombosis. Using a large-scale epidemiological approach, we identified eosinophil cationic protein (ECP) as independent and predictive risk factor for thrombotic events in humans. Concurrent experiments showed that eosinophils contributed to intravascular thrombosis by exhibiting a strong endogenous thrombin-generation capacity, which relied on the enzymatic generation and active provision of a pro-coagulant phospholipid-surface enriched in 12/15-lipoxygenase (12/15-LO)-derived hydroxyeicosatetraenoic acid-phosphatidylethanolamines. Our findings reveal a previously unrecognized role of eosinophils and enzymatic lipid oxidation as regulatory elements that facilitate both hemostasis and thrombosis in response to vascular injury, thus identifying promising new targets for the treatment of thrombotic disease.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Publisher: Rockefeller University Press
ISSN: 0022-1007
Funders: Wellcome Trust, British Heart Foundation
Date of First Compliant Deposit: 24 April 2017
Date of Acceptance: 19 April 2017
Last Modified: 22 Dec 2017 18:50
URI: http://orca.cf.ac.uk/id/eprint/100036

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