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

Zane Kaplan, Alessandro Zarpellon, Imala Alwis, Yu-Ping Yuan, James David McFadyen, Mehran Ghasemzadeh, Simone Marianne Schoenwaelder, Zaverio M Ruggeri, Shaun Jackson

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40 Citations (Scopus)

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, GPIba 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 GPIba, as seen in mice with abrogated thrombin-platelet GPIba binding (hGPIba D277N). 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, GPIba and fibrin. Dysregulation of this checkpoint mechanism is likely to contribute to the development of thromboinflammatory disorders.
Original languageEnglish
Pages (from-to)1 - 13
Number of pages13
JournalNature Communications
Volume6
Issue number(Art. No: 7835)
DOIs
Publication statusPublished - 2015

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