367 Inducible loss of claudin-1 in keratinocytes leads to the induction of itch transmitted by multiple types of sensory nerves

Claudin-1 encoded by the Cldn1 gene is a central component of tight junctions in the epidermal granular layer. Barrier disruption in the epidermis is a well-known pathogenic factor of atopic dermatitis (AD), and it has been reported that reduced claudin-1 expression causes AD-like morphological manifestation and inflammation in the mouse skin. However, whether claudin-1 depletion in adult mice causes chronic itch is not known. In this study, we generated Cldn1 conditional knockout (cKO) mice in which depletion of claudin-1 could be induced selectively in keratinocytes by injections of tamoxifen. We found that these mice showed chronic scratching behavior after tamoxifen injections. To understand whether the itchiness of the Cldn1 cKO mice was induced by inflammatory chemical mediators, we investigated the involvement of C fiber sensory nerves, which are responsible for transmission of chemically induced itch. For this purpose, we crossed the Cldn1 cKO mice with mice in which tetanus toxin was expressed in C fiber sensory neurons to inhibit their synaptic transmission. Unexpectedly, we found that initial scratching behavior elicited after the tamoxifen treatment was not suppressed by the absence of C fiber transmission. However, scratching behavior elicited by claudin-1 depletion without C fiber transmission was not chronic and disappeared in a week. These data suggest that the epidermal barrier disruption by the loss of keratinocyte claudin-1 first leads to C fiber-independent itch, which may be induced by mechanical stimuli and transmitted by Ab fiber sensory nerves, and subsequently leads to C fiber-dependent itch induced by chemical mediators.