Research article

Essential role of platelet activation via protease activated receptor 4 in tissue factor-initiated inflammation

Nathalie Busso¹ , Veronique Chobaz-Péclat¹ , Justin Hamilton^2,3 , Pieter Spee⁴ , Nicolai Wagtmann⁴ and Alexander So¹

¹Laboratoire de Rhumatologie, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland

²Cardiovascular Research Institute, University of California at San Francisco, Parnassus Avenue, 94143, San Francisco, California, USA

³Monash University, Australian Centre for Blood Diseases, 89 Commercial Rd, Melbourne, Victoria 3004. Australia

⁴Biopharmaceuticals Biology, Novo Nordisk R&D, 2760 Bagsvaerd, Denmark

author email corresponding author email

Arthritis Research & Therapy 2008, 10:R42doi:10.1186/ar2400

Published:	15 April 2008

Abstract

Introduction

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).

Methods

We induced extravascular inflammation by injection of recombinant soluble murine TF (sTF_1–219) 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.

Results

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.

Conclusion

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.