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

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. In this study, we demonstrate an unexpected role of eosinophils during plasmatic coagulation, hemostasis, and thrombosis. Using a large-scale epidemiological approach, we identified eosinophil cationic protein as an 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 that relied on the enzymatic generation and active provision of a procoagulant phospholipid surface enriched in 12/15-lipoxygenase-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.

• Authors: Stefan Uderhardt, Jochen A Ackermann, Tobias Fillep, Victoria J Hammond, Johann Willeit, Peter Santer, Manuel Mayr, Markus Biburger, Meike Miller, Katie R Zellner, Konstantin Stark, Alexander Zarbock, Jan Rossaint, Irene Schubert, Dirk Mielenz, Barbara Dietel, Dorette Raaz-Schrauder, Cihan Ay, Thomas Gremmel, Johannes Thaler, Christian Heim, Martin Herrmann, Peter W Collins, Gernot Schabbauer, Nigel Mackman, David Voehringer, Jerry L Nadler, James J Lee, Steffen Massberg, Manfred Rauh, Stefan Kiechl, Georg Schett, Valerie B O'Donnell, Gerhard Krönke
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 214 Issue 7 Pg. 2121-2138 (Jul 03 2017) ISSN: 1540-9538 [Electronic] United States
• PMID: 28566277 (Publication Type: Journal Article)
• Copyright: © 2017 Uderhardt et al.

Chemical References

• 12-15-lipoxygenase
• Hydroxyeicosatetraenoic Acids
• Lipids
• Phosphatidylethanolamines
• Arachidonate 12-Lipoxygenase
• Arachidonate 15-Lipoxygenase
• Eosinophil Cationic Protein
• Thrombin

Topics

• Adult
• Aged
• Animals
• Arachidonate 12-Lipoxygenase (genetics, metabolism)
• Arachidonate 15-Lipoxygenase (genetics, metabolism)
• Atherosclerosis (diagnosis, metabolism)
• Blood Coagulation
• Blotting, Western
• Cells, Cultured
• Eosinophil Cationic Protein (metabolism)
• Eosinophils (metabolism)
• Hemostasis
• Humans
• Hydroxyeicosatetraenoic Acids (metabolism)
• Lipids (analysis)
• Logistic Models
• Mice, Inbred C57BL
• Mice, Knockout
• Middle Aged
• Oxidation-Reduction
• Phosphatidylethanolamines (metabolism)
• Prospective Studies
• Reverse Transcriptase Polymerase Chain Reaction
• Risk Factors
• Thrombin (metabolism)
• Thrombosis (metabolism)