Essential role of platelet activation via protease activated receptor 4 in tissue factor-initiated inflammation
1 Laboratoire de Rhumatologie, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland
2 Cardiovascular Research Institute, University of California at San Francisco, Parnassus Avenue, 94143, San Francisco, California, USA
3 Monash University, Australian Centre for Blood Diseases, 89 Commercial Rd, Melbourne, Victoria 3004. Australia
4 Biopharmaceuticals Biology, Novo Nordisk R&D, 2760 Bagsvaerd, Denmark
Arthritis Research & Therapy 2008, 10:R42 doi:10.1186/ar2400Published: 15 April 2008
Tissue factor (TF) activation of the coagulation proteases enhances inflammation in animal models of arthritis and endotoxemia, but the mechanism of this effect is not yet fully understood – in particular, whether this is primarily due to fibrin formation or through activation of protease activated receptors (PARs).
We induced extravascular inflammation by injection of recombinant soluble murine TF (sTF1–219) in the hind paw. The effects of thrombin inhibition, fibrinogen and platelet depletion were evaluated, as well as the effects of PAR deficiency using knockout mice deficient for each of the PARs.
Injection of soluble TF provoked a rapid onset of paw swelling. Inflammation was confirmed histologically and by increased serum IL-6 levels. Inflammation was significantly reduced by depletion of fibrinogen (P < 0.05) or platelets (P = 0.015), and by treatment with hirudin (P = 0.04) or an inhibitor of activated factor VII (P < 0.001) compared with controls. PAR-4-deficient mice exhibited significantly reduced paw swelling (P = 0.003). In contrast, a deficiency in either PAR-1, PAR-2 or PAR-3 did not affect the inflammatory response to soluble TF injection.
Our results show that soluble TF induces acute inflammation through a thrombin-dependent pathway and both fibrin deposition and platelet activation are essential steps in this process. The activation of PAR-4 on platelets is crucial and the other PARs do not play a major role in soluble TF-induced inflammation.