Protease‐activated receptor 2 mediates the proinflammatory effects of synovial mast cells

• Published in: Arthritis and rheumatism 2007-11, Vol.56 (11), p.3532-3540
• Main Authors: Palmer, H. S., Kelso, E. B., Lockhart, J. C., Sommerhoff, C. P., Plevin, R., Goh, F. G., Ferrell, W. R.
• Format: Article
• Language: English
• Subjects: Animals; Arthritis, Rheumatoid - immunology; Arthritis, Rheumatoid - metabolism; Arthritis, Rheumatoid - pathology; Biological and medical sciences; Cardiovascular system; Cell Degranulation - immunology; Diseases of the osteoarticular system; Edema - immunology; Edema - metabolism; Edema - pathology; Hyperemia - immunology; Hyperemia - metabolism; Hyperemia - pathology; Immunohistochemistry; Inflammatory joint diseases; Investigative techniques, diagnostic techniques (general aspects); Knee Joint - blood supply; Knee Joint - immunology; Knee Joint - pathology; Laser-Doppler Flowmetry; Mast Cells - enzymology; Mast Cells - immunology; Mast Cells - pathology; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Miscellaneous. Osteoarticular involvement in other diseases; Receptor, PAR-2 - genetics; Receptor, PAR-2 - immunology; Receptor, PAR-2 - metabolism; Synovial Membrane - immunology; Synovial Membrane - pathology; Tryptases - metabolism; Ultrasonic investigative techniques
• ISSN: 0004-3591; 1529-0131
• DOI: 10.1002/art.22936

Objective Mast cells are hypothesized to play a role in the pathogenesis of rheumatoid arthritis (RA) by mechanisms requiring elucidation. Tryptase released from these cells can activate protease‐activated receptor 2 (PAR‐2), which was recently shown to have proinflammatory actions. The purpose of this study was to examine the relationship between synovial mast cells and PAR‐2. Mast cell proximity to PAR‐2–expressing cells was investigated in RA synovium. In murine studies, we assessed the capacity of mast cell tryptase to mediate synovial proinflammatory responses via PAR‐2 and whether degranulating mast cells induced synovial hyperemia by PAR‐2 activation. Methods RA synovial tissue was examined by immunohistochemistry. PAR‐2+/+ and PAR‐2−/− C57BL/6J mice were used to investigate the PAR‐2 dependence of compound 48/80–induced synovial hyperemia, as measured by laser Doppler imaging, and joint swelling and hyperemic responses to recombinant human β‐tryptase. Results Mast cells and synovial lining cells staining for PAR‐2 were colocalized in RA articular tissue. Compound 48/80 administration resulted in vasodilatation in PAR‐2+/+ mice but not in PAR‐2−/− mice, which showed a vasoconstrictor response. Eliminating the 5‐hydroxytryptamine–mediated component of this response with methysergide unveiled an enhanced PAR‐2–mediated vasodilatation to compound 48/80 in PAR‐2+/+ mice and ablated the vasoconstrictor response in PAR‐2−/− mice. Treatment with β‐tryptase resulted in dose‐dependent knee joint swelling and synovial vasodilatation in PAR‐2+/+ mice but not PAR‐2−/− mice. Conclusion This in vivo study is the first to explore the relationship between synovial mast cells and PAR‐2. Our results support the hypothesis that mast cells contribute to the pathogenesis of inflammatory arthritis through PAR‐2 activation via release of mast cell tryptase.