Proteinase‐activated receptor‐2 mediates itch: a novel pathway for pruritus in human skin

Abstract

Proteinase‐activated receptors are G‐protein‐coupled receptors with seven‐transmembrane domains activated by serine proteinases. PAR‐2 is a receptor for mast cell tryptase, house dust mite allergens, bacterial antigens and trypsin, for example, indicating a role of PAR‐2 during inflammation and immune responses. In the skin, PAR‐2 is expressed by keratinocytes, endothelial cells, certain immune cells and nerves, suggesting a broad regulatory role of proteases in the skin. Recently, PAR‐2 has been demonstrated to be involved in neurogenic inflammation. Therefore, we examined whether neuronal PAR‐2 may be involved in pruritus of human skin. The endogenous PAR‐2 agonist tryptase was increased up to fourfold in atopic dermatitis (AD) patients. PAR‐2 was markedly enhanced on primary afferent nerve fibres in skin biopsies of AD patients. Intracutaneous injection of endogenous PAR‐2 agonists provoked enhanced and prolonged itch when applied intralesionally. Interestingly, itch upon mast cell degranulation prevailed despite local antihistamines in AD patients only. Thus, we identified enhanced PAR‐2 signalling as a new link between inflammatory and sensory phenomena in AD patients. PAR‐2 antagonists, thus, represent a promising therapeutic target for the treatment of cutaneous neurogenic inflammation and pruritus.