Journal
IMMUNITY
Volume 34, Issue 2, Pages 258-268Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2011.02.008
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Funding
- Vetenskapsradet [K2010-64X-21462-01-3]
- Hjart Lungfonden [20090642]
- Stockholms lans landsting (ALF) [20090540]
- Stiftung fur Pathobiochemie und Molekulare Diagnostik of the DGKL,
- Cancerfonden [100615]
- Federal Ministry of Education and Research (BMBF)
- Rubicon fellowship [825-10-012]
- Netherlands Organisation for Scientific Research (NWO)
- Margarete Waitz-foundation, Mainz
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Activated mast cells trigger edema in allergic and inflammatory disease. We report a paracrine mechanism by which mast cell-released heparin increases vascular permeability in vivo. Heparin activated the protease factor XII, which initiates bradykinin formation in plasma. Targeting factor XII or kinin B2 receptors abolished heparin-triggered leukocyte-endothelium adhesion and interfered with a mast cell-driven drop in blood pressure in rodents. Intravital laser scanning microscopy and tracer measurements showed heparin-driven fluid extravasation in mouse skin microvessels. Ablation of factor XII or kinin B2 receptors abolished heparin-induced skin edema and protected mice from allergen-activated mast cell-driven leakage. In contrast, heparin and activated mast cells induced excessive edema in mice deficient in the major inhibitor of factor XII, Cl esterase inhibitor. Allergen exposure triggered edema attacks in hereditary angioedema patients, lacking Cl esterase inhibitor. The data indicate that heparin-initiated bradykinin formation plays a fundamental role in mast cell-mediated diseases.
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