Involvement of Serine Protease and Proteinase-Activated Receptor 2 in Dermatophyte-Associated Itch in Mice

Abstract

We investigated the involvement of serine protease and proteinase-activated receptor 2 (PAR(2)) 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 PAR(2) receptor antagonist FSLLRY-NH(2). ADV extract-induced scratching was not inhibited by the H(1) 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 PAR(2) 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 PAR(2) receptor. The present results suggest that serine protease secreted by dermatophytes causes itching through activation of the PAR(2) receptors, which may be a causal mechanism of dernatophytosis itch.