Background/Purpose: Proteinase activated receptors (PARs) are a family of G protein-coupled receptors that signal by enzymatic cleavage of the receptor in a specific extracellular domain. Since PAR-4 has been shown to cause pain and inflammation in synovial joints, the aim of this study was to examine the effect of PAR-4 activation on leukocyte kinetics in the synovial microvasculature.

Methods: Male c57/bl6 mice were deeply anaesthetised and the right knee joint was exposed. An intravenous injection of 0.05% rhodamine was administered to label circulating leukocytes. Intravital microscopy was used to measure leukocyte trafficking in the joint in response to local administration of the PAR-4 agonist AYPGKF-NH2 (50mM). Comparisons were made in wild-type and P-selectin knockout mice. The effect of the PAR-4 antagonist pepducin p4Pal10 on leukocyte kinetics in an adjuvant monoarthritic knee was also assessed.

Results: In wild-type animals, AYPGKF-NH2 caused a gradual increase in leukocyte rolling and adherence which was not present in P-selectin knockout mice (P<0.0001, n=8). Treatment of arthritic mice with pepducin p4Pal10 reduced leukocyte rolling and accumulation in the joint (P<0.0001).

Conclusion: Activation of PAR-4 in rat knee joints causes leukocyte rolling and adhesion that is P-selectin-dependent. In an arthritic joint, blockade of PAR-4 with pepducin p4Pal10 reversed these pro-inflammatory changes indicating that PAR-4 antagonism can have an anti-inflammatory outcome.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/proteinase-activated-receptor-4-stimulation-promotes-leukocyte-adhesion-in-the-rat-knee-joint/