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

M. Steinhoff; N. Vergnolle; S. H. Young; M. Tognetto; S. Amadesi; H. S. Ennes; M. Trevisani; M. D. Hollenberg; J. L. Wallace; G. H. Caughey; S. E. Mitchell; L. M. Williams; P. Geppetti; E. A. Mayer; N. W. Bunnett

doi:10.1038/72247

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

M. Steinhoff, N. Vergnolle, S. H. Young, M. Tognetto, S. Amadesi, H. S. Ennes, M. Trevisani, M. D. Hollenberg, J. L. Wallace, G. H. Caughey, S. E. Mitchell, L. M. Williams, P. Geppetti, E. A. Mayer, N. W. Bunnett

Molecular Pathobiology

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Pages (from-to)	151-158
Number of pages	8
Journal	Nature Medicine
Volume	6
Issue number	2
DOIs	https://doi.org/10.1038/72247
State	Published - Feb 2000

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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Steinhoff, M., Vergnolle, N., Young, S. H., Tognetto, M., Amadesi, S., Ennes, H. S., Trevisani, M., Hollenberg, M. D., Wallace, J. L., Caughey, G. H., Mitchell, S. E., Williams, L. M., Geppetti, P., Mayer, E. A., & Bunnett, N. W. (2000). Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism. Nature Medicine, 6(2), 151-158. https://doi.org/10.1038/72247

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title = "Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism",

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.",

author = "M. Steinhoff and N. Vergnolle and Young, {S. H.} and M. Tognetto and S. Amadesi and Ennes, {H. S.} and M. Trevisani and Hollenberg, {M. D.} and Wallace, {J. L.} and Caughey, {G. H.} and Mitchell, {S. E.} and Williams, {L. M.} and P. Geppetti and Mayer, {E. A.} and Bunnett, {N. W.}",

note = "Funding Information: Acknowledgments Supported by the National Institutes of Health, Crohn{\textquoteright}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.",

year = "2000",

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doi = "10.1038/72247",

language = "English (US)",

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AU - Steinhoff, M.

AU - Vergnolle, N.

AU - Young, S. H.

AU - Tognetto, M.

AU - Amadesi, S.

AU - Ennes, H. S.

AU - Trevisani, M.

AU - Hollenberg, M. D.

AU - Wallace, J. L.

AU - Caughey, G. H.

AU - Mitchell, S. E.

AU - Williams, L. M.

AU - Geppetti, P.

AU - Mayer, E. A.

AU - Bunnett, N. W.

N1 - Funding Information: Acknowledgments 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.

PY - 2000/2

Y1 - 2000/2

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

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