Involvement of serine protease and proteinase-activated receptor 2 in dermatophyte-associated itch in mice

We investigated the involvement of serine protease and proteinase-activated receptor 2 (PAR₂) in dermatophyte-induced itch in mice. An intradermal injection of an extract of the dermatophyte Arthroderma vanbreuseghemii (ADV) induced hind-paw scratching, an itch-related behavior. ADV extract-induced scratching was inhibited by the opioid receptor antagonists naloxone and naltrexone, the serine protease inhibitor nafamostat mesylate, and the PAR₂ receptor antagonist FSLLRY-NH₂. ADV extract-induced scratching was not inhibited by the H₁ histamine receptor antagonist terfenadine or by mast cell deficiency. Heat pretreatment of the ADV extract markedly reduced the scratch-inducing and serine protease activities. Proteolytic cleavage within the extracellular N terminus of the PAR₂ receptor exposes a sequence that serves as a tethered ligand for the receptor. The ADV extract as well as tryptase and trypsin cleaved a synthetic N-terminal peptide of the PAR₂ receptor. The present results suggest that serine protease secreted by dermatophytes causes itching through activation of the PAR₂ receptors, which may be a causal mechanism of dernatophytosis itch.