Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism.
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.
Steinhoff
M
M
Department of Surgery and Physiology, University of California, San Francisco, CA 94143, USA.
Vergnolle
N
N
Young
S H
SH
Tognetto
M
M
Amadesi
S
S
Ennes
H S
HS
Trevisani
M
M
Hollenberg
M D
MD
Wallace
J L
JL
Caughey
G H
GH
Mitchell
S E
SE
Williams
L M
LM
Geppetti
P
P
Mayer
E A
EA
Bunnett
N W
NW
D000818:Animals; D001483:Base Sequence; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D053818:Chymases; D015342:DNA Probes; D005727:Ganglia, Spinal / Q000378:metabolism / Q000473:pathology; D006801:Humans; D017403:In Situ Hybridization; D007249:Inflammation / Q000209:etiology*; D008297:Male; D009474:Neurons / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D044464:Receptor, PAR-2; D018179:Receptors, Thrombin / Q000819:agonists* / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism; D015398:Signal Transduction; D013373:Substance P / Q000378:metabolism; D014357:Trypsin / Q000378:metabolism; D053802:Tryptases
D015342:DNA Probes; D044464:Receptor, PAR-2; D018179:Receptors, Thrombin; D013373:Substance P; D012697:Serine Endopeptidases; C083294:chymase 2; D053818:Chymases; D014357:Trypsin; C509223:Tpsab1 protein, rat; C509221:Tpsb2 protein, rat; D053802:Tryptases; D015740:Calcitonin Gene-Related Peptide