319 The role of TLR-3 in the itch-scratch cycle of nodular prurigo - new insights into innate immune mechanisms of peripheral itch sensitization

Itch (pruritus) is the most common symptom in dermatology, and is associated with very significant physical and psychological morbidity. While the pathophysiology of acute itch is fairly well-researched, our understanding of persistant, chronic itch is much poorer. Recent studies have demonstrated that among Toll-like receptors (TLR, cellular sensors that recognize molecular danger signals associated with exogenous or endogenous threats) TLR3 is significant in the regulation of itch signalling. Since TLR3 not only acts as an innate biosensor of viral pathogens but also responds to endogenous damage associated molecular patterns including RNA released from injured epidermal keratinocytes, we hypothesise that scratching, which leads to epidermal damage and the release of RNA from keratinocytes contributes to the peripheral sensitization of itch via the activation of TLR3 in chronically scratched skin of patients with nodular prurigo. Using normal human epidermal keratinocytes (NHEKs) stimulated with polyinosinic:polycytidylic acid (poly I:C) we showed that keratinocytes release IL-6 and Endothelin which could contribute to the inflammatory milieu and to itch transduction, respectively. We have also found that TLR3 stimulation upregulates TLR3 expression in vitro, which hints at a possible positive feedback cycle in chronically scratched skin. In line with these results the expression of TLR3 was significantly increased in the lesional skin of patients with prurigo nodularis (mean VAS score 6.8) compared with perilesional skin and skin of healthy controls. Therefore TLR3 may act as an important receptor in the itch-scratch-cycle, acting not only as a sensor of injured, scratched epidermal skin but also, through its increased expression and release of potent pruritogens(ET-1) and proinflammatory cytokines.