Thrombin-dependent intravascular leukocyte trafficking regulated by fibrin and the platelet receptors GPIb and PAR4

Zane S. Kaplan, Alessandro Zarpellon, Imala Alwis, Yuping Yuan, James McFadyen, Mehran Ghasemzadeh, Simone M. Schoenwaelder, Zaverio M. Ruggeri and Shaun P. Jackson ()
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Zane S. Kaplan: Australian Centre for Blood Diseases, Monash University
Alessandro Zarpellon: The Scripps Research Institute
Imala Alwis: Australian Centre for Blood Diseases, Monash University
Yuping Yuan: Australian Centre for Blood Diseases, Monash University
James McFadyen: Australian Centre for Blood Diseases, Monash University
Mehran Ghasemzadeh: Australian Centre for Blood Diseases, Monash University
Simone M. Schoenwaelder: Australian Centre for Blood Diseases, Monash University
Zaverio M. Ruggeri: The Scripps Research Institute
Shaun P. Jackson: Australian Centre for Blood Diseases, Monash University

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: Abstract Thrombin is a central regulator of leukocyte recruitment and inflammation at sites of vascular injury, a function thought to involve primarily endothelial PAR cleavage. Here we demonstrate the existence of a distinct leukocyte-trafficking mechanism regulated by components of the haemostatic system, including platelet PAR4, GPIbα and fibrin. Utilizing a mouse endothelial injury model we show that thrombin cleavage of platelet PAR4 promotes leukocyte recruitment to sites of vascular injury. This process is negatively regulated by GPIbα, as seen in mice with abrogated thrombin-platelet GPIbα binding (hGPIbαD277N). In addition, we demonstrate that fibrin limits leukocyte trafficking by forming a physical barrier to intravascular leukocyte migration. These studies demonstrate a distinct ‘checkpoint’ mechanism of leukocyte trafficking involving balanced thrombin interactions with PAR4, GPIbα and fibrin. Dysregulation of this checkpoint mechanism is likely to contribute to the development of thromboinflammatory disorders.

Date: 2015
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8835

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DOI: 10.1038/ncomms8835

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