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Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism

Nature Medicine volume 6, pages 151–158 (2000)Cite this article

Abstract

Trypsin and mast cell tryptase cleave proteinase-activated receptor 2 and, by unknown mechanisms, induce widespread inflammation. We found that a large proportion of primary spinal afferent neurons, which express proteinase-activated receptor 2, also contain the proinflammatory neuropeptides calcitonin gene-related peptide and substance P. Trypsin and tryptase directly signal to neurons to stimulate release of these neuropeptides, which mediate inflammatory edema induced by agonists of proteinase-activated receptor 2. This new mechanism of protease-induced neurogenic inflammation may contribute to the proinflammatory effects of mast cells in human disease. Thus, tryptase inhibitors and antagonists of proteinase-activated receptor 2 may be useful anti-inflammatory agents.

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Figure 1: Localization and expression of PAR2-LI and PAR2 mRNA in DRG.
Figure 2: Expression of PAR2-LI and of functional PAR2 by DRG neurons in culture.
Figure 3: PAR2-mediated Ca2+ mobilization in DRG neurons in culture.
Figure 4: PAR2-mediated release of CGRP-LI (a) and SP-LI (b) from superfused dorsal horn of the spinal cord, urinary bladder, and atrium.
Figure 5: Neurogenic mechanism of PAR2-induced edema of the rat paw. a–c .
Figure 6: PAR2-induced inflammation of the rat paw.
Figure 7: Neurogenic mechanisms of PAR2-induced edema.

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Acknowledgements

Supported by the National Institutes of Health, Crohn's and Colitis Foundation of America, the Medical Research Council of Canada, North Atlantic Treaty Organization (NATO), and St. Anna Hospital, Ferrara, Italy. We thank V. Ossovskaya, E. Grady, and A. Steinhoff for valuable advice.

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Author notes

  1. M. Steinhoff, N. Vergnolle, S.H. Young and M. Tognetto: M.S., N.V., S.H.Y. and M.T. contributed equally to this study.

Authors and Affiliations

  1. Departments of Surgery and Physiology, University of California, 513 Parnassus Avenue, San Francisco , 94143, California, USA

    M. Steinhoff & N.W. Bunnett

  2. Department of Medicine and the Cardiovascular Research Institute, University of California, San Francisco, 94143, California, USA

    G.H. Caughey

  3. Department of Medicine and CURE VA/UCLA Digestive Diseases Research Center, University of California, Los Angeles, 90073, California, USA

    S.H. Young, H.S. Ennes & E.A. Mayer

  4. Department of Pharmacology and Therapeutics, University of Calgary, Calgary, AB T2N 4N1, Canada

    N. Vergnolle, M.D. Hollenberg & J.L. Wallace

  5. Rowett Research Institute, Aberdeen, LS21 9JT, UK

    S.E. Mitchell & L.M. Williams

  6. Department of Experimental and Clinical Medicine, Headache Center, Pharmacology Section, University of Ferrara, Ferrara, 44100, Italy

    M. Tognetto, S. Amadesi, M. Trevisani & P. Geppetti

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Correspondence to N.W. Bunnett.

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Steinhoff, M., Vergnolle, N., Young, S. et al. Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism. Nat Med 6, 151–158 (2000). https://doi.org/10.1038/72247

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