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

H. S. Palmer, E. B. Kelso, J. C. Lockhart, C. P. Sommerhoff, R. Plevin, F. G. Goh, W. R. Ferrell

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)3532-3540
Number of pages9
JournalArthritis and Rheumatism
Volume56
Issue number11
DOIs
Publication statusPublished - 1 Nov 2007

Keywords

  • synovial mast cells
  • protease‐activated receptor 2

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