Scratching Counteracts IL-13 Signaling by Upregulating the Decoy Receptor IL-13Rα2 in Keratinocytes

The vicious itch-scratch cycle is a cardinal feature of atopic dermatitis (AD), in which IL-13 signaling plays a dominant role. Keratinocytes express two receptors: The heterodimeric IL-4R alpha/IL-13R alpha 1 and IL-13R alpha 2. The former one transduces a functional IL-13 signal, whereas the latter IL-13R alpha 2 works as a nonfunctional decoy receptor. To examine whether scratch injury affects the expression of IL-4R alpha, IL-13R alpha 1, and IL-13R alpha 2, we scratched confluent keratinocyte sheets and examined the expression of three IL-13 receptors using quantitative real-time PCR (qRT-PCR) and immunofluorescence techniques. Scratch injuries significantly upregulated the expression of IL13RA2 in a scratch line number-dependent manner. Scratch-induced IL13RA2 upregulation was synergistically enhanced in the simultaneous presence of IL-13. In contrast, scratch injuries did not alter the expression of IL4R and IL13RA1, even in the presence of IL-13. Scratch-induced IL13RA2 expression was dependent on ERK1/2 and p38 MAPK signals. The expression of IL-13R alpha 2 protein was indeed augmented in the scratch edge area and was also overexpressed in lichenified lesional AD skin. IL-13 inhibited the expression of involucrin, an important epidermal terminal differentiation molecule. IL-13-mediated downregulation of involucrin was attenuated in IL-13R alpha 2-overexpressed keratinocytes, confirming the decoy function of IL-13R alpha 2. Our findings indicate that scratching upregulates the expression of the IL-13 decoy receptor IL-13R alpha 2 and counteracts IL-13 signaling.