Thrombin-dependent intravascular leukocyte trafficking regulated by fibrin and the platelet receptors GPIb and PAR4
Male
0301 basic medicine
Fibrinolysis
Thrombin
Endothelial Cells
Platelet Activation
Mice, Inbred C57BL
Mice
03 medical and health sciences
Platelet Glycoprotein GPIb-IX Complex
Cell Movement
Models, Animal
Leukocytes
Animals
Humans
Receptors, Thrombin
DOI:
10.1038/ncomms8835
Publication Date:
2015-07-23T12:33:23Z
AUTHORS (9)
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 (hGPIbα(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, GPIbα and fibrin. Dysregulation of this checkpoint mechanism is likely to contribute to the development of thromboinflammatory disorders.
SUPPLEMENTAL MATERIAL
Coming soon ....
REFERENCES (70)
CITATIONS (68)
EXTERNAL LINKS
PlumX Metrics
RECOMMENDATIONS
FAIR ASSESSMENT
Coming soon ....
JUPYTER LAB
Coming soon ....