title: Thrombin-dependent intravascular leukocyte trafficking regulated by fibrin and the platelet receptors GPIb and PAR4.
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.
authors.affiliation: Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria 3004, Australia.
authors.forename: Zane S
authors.initials: ZS
authors.lastname: Kaplan
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Zarpellon
authors.affiliation: Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria 3004, Australia.|Heart Research Institute &Charles Perkins Centre, The University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Imala
authors.initials: I
authors.lastname: Alwis
authors.affiliation: Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria 3004, Australia.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria 3004, Australia.
authors.forename: James
authors.initials: J
authors.lastname: McFadyen
authors.affiliation: Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria 3004, Australia.|Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran.
authors.forename: Mehran
authors.initials: M
authors.lastname: Ghasemzadeh
authors.affiliation: Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria 3004, Australia.|Heart Research Institute &Charles Perkins Centre, The University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Simone M
authors.initials: SM
authors.lastname: Schoenwaelder
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Zaverio M
authors.initials: ZM
authors.lastname: Ruggeri
authors.affiliation: Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria 3004, Australia.|Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA.|Heart Research Institute &Charles Perkins Centre, The University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Shaun P
authors.initials: SP
authors.lastname: Jackson
mesh_terms: D000818:Animals; D002465:Cell Movement; D042783:Endothelial Cells / Q000502:physiology; D005342:Fibrinolysis; D006801:Humans; D007962:Leukocytes / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D015539:Platelet Activation; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism*; D018179:Receptors, Thrombin / Q000378:metabolism*; D013917:Thrombin / Q000378:metabolism*
chemical_list: D019038:Platelet Glycoprotein GPIb-IX Complex; D018179:Receptors, Thrombin; C094990:adhesion receptor; D013917:Thrombin; C112908:protease-activated receptor 4