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

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737 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

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