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 larg e proportion of primary spinal afferent neurons, which express proteinase-a ctivated receptor 2, also contain the proinflammatory neuropeptides calcito nin gene-related peptide and substance P. Trypsin and tryptase directly sig nal to neurons to stimulate release of these neuropeptides, which mediate i nflammatory edema induced by agonists of proteinase-activated receptor 2. T his new mechanism of protease-induced neurogenic inflammation may contribut e to the proinflammatory effects of mast cells in human disease. Thus, tryp tase inhibitors and antagonists of proteinase-activated receptor 2 may be u seful anti-inflammatory agents.