Protease-activated receptor 2 mediates the proinflammatory effects of synovial mast cells
Protease-activated receptor 2 mediates the proinflammatory effects of synovial mast cells
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DOI：
10.1002/art.22936
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发表时间：
2007-11-01
影响因子：
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通讯作者：
Ferrell, W. R.
中科院分区：
文献类型：
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作者：
Palmer, H. S.;Kelso, E. B.;Ferrell, W. R.
Objective.肥大细胞在类风湿性关节炎（RA）的发病机制中起着重要的作用。从这些细胞释放的类胰蛋白酶可以激活蛋白酶激活受体2（PAR-2），其最近被证明具有促炎作用。本研究的目的是研究滑膜肥大细胞和PAR-2之间的关系。在RA滑膜中研究肥大细胞与PAR-2表达细胞的接近性。在小鼠研究中，我们评估了肥大细胞类胰蛋白酶通过PAR-2介导滑膜促炎反应的能力，以及肥大细胞脱粒是否通过PAR-2激活诱导滑膜充血。用免疫组化法检测RA滑膜组织。使用PAR-2（+/+）和PAR-2（-/-）C57 BL/6 J小鼠研究化合物48/80诱导的滑膜充血的PAR-2依赖性（如通过激光多普勒成像测量的）以及对重组人β-类胰蛋白酶的关节肿胀和充血反应。肥大细胞和滑膜衬里细胞共定位于RA关节组织中的PAR-2染色。化合物48/80给药导致PAR-2（+/+）小鼠的血管舒张，但不导致PAR-2（-/-）小鼠的血管舒张，PAR-2（-/-）小鼠显示血管收缩反应。用麦角新碱消除该反应的5-羟色胺介导的组分揭示了PAR-2介导的PAR-2（+/+）小鼠中化合物48/80的血管舒张增强，并且消除了PAR-2（-/-）小鼠中的血管收缩反应。β-类胰蛋白酶处理导致PAR-2（+/+）小鼠膝关节肿胀和滑膜血管扩张呈剂量依赖性，但PAR-2（-/-）小鼠则无此作用。这项体内研究是第一次探讨滑膜肥大细胞和PAR-2之间的关系。我们的研究结果支持了肥大细胞通过释放肥大细胞类胰蛋白酶激活PAR-2参与炎症性关节炎发病机制的假设。
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 beta-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 PAR2(+/+) mice and ablated the vasoconstrictor response in PAR-2(-/-) mice. Treatment with beta-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.