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, Sharon Elizabeth Mitchell, Lynda Williams, P Geppetti, E A Mayer, N W Bunnett

Research output: Contribution to journalArticle

722 Citations (Scopus)

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 languageEnglish
Pages (from-to)151-158
Number of pages8
JournalNature Medicine
Volume6
Issue number2
DOIs
Publication statusPublished - Feb 2000

Keywords

  • gene-related peptide
  • mast-cell tryptase
  • spinal dorsal horn
  • substance-P
  • endothelial-cells
  • thrombin receptor
  • in-vitro
  • skin
  • vasodilator
  • CGRP

Cite this

Steinhoff, M., Vergnolle, N., Young, S. H., Tognetto, M., Amadesi, S., Ennes, H. S., ... 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

Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism. / 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, Sharon Elizabeth; Williams, Lynda; Geppetti, P ; Mayer, E A ; Bunnett, N W .

In: Nature Medicine, Vol. 6, No. 2, 02.2000, p. 151-158.

Research output: Contribution to journalArticle

Steinhoff, M, Vergnolle, N, Young, SH, Tognetto, M, Amadesi, S, Ennes, HS, Trevisani, M, Hollenberg, MD, Wallace, JL, Caughey, GH, Mitchell, SE, Williams, L, Geppetti, P, Mayer, EA & Bunnett, NW 2000, 'Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism', Nature Medicine, vol. 6, no. 2, pp. 151-158. https://doi.org/10.1038/72247
Steinhoff M, Vergnolle N, Young SH, Tognetto M, Amadesi S, Ennes HS et al. Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism. Nature Medicine. 2000 Feb;6(2):151-158. https://doi.org/10.1038/72247
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, Sharon Elizabeth ; Williams, Lynda ; Geppetti, P ; Mayer, E A ; Bunnett, N W . / Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism. In: Nature Medicine. 2000 ; Vol. 6, No. 2. pp. 151-158.
@article{6469e1f3a0b449498878a9822e91d6dd,
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.",
keywords = "gene-related peptide, mast-cell tryptase, spinal dorsal horn, substance-P, endothelial-cells, thrombin receptor, in-vitro, skin, vasodilator, CGRP",
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, {Sharon Elizabeth} and Lynda Williams and P Geppetti and Mayer, {E A} and Bunnett, {N W}",
year = "2000",
month = "2",
doi = "10.1038/72247",
language = "English",
volume = "6",
pages = "151--158",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "2",

}

TY - JOUR

T1 - Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism

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, Sharon Elizabeth

AU - Williams, Lynda

AU - Geppetti, P

AU - Mayer, E A

AU - Bunnett, N W

PY - 2000/2

Y1 - 2000/2

N2 - 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.

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.

KW - gene-related peptide

KW - mast-cell tryptase

KW - spinal dorsal horn

KW - substance-P

KW - endothelial-cells

KW - thrombin receptor

KW - in-vitro

KW - skin

KW - vasodilator

KW - CGRP

U2 - 10.1038/72247

DO - 10.1038/72247

M3 - Article

VL - 6

SP - 151

EP - 158

JO - Nature Medicine

JF - Nature Medicine

SN - 1078-8956

IS - 2

ER -