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

Dugarmaa Ulzii,Kazuhisa Furue,Akiko Hashimoto-Hachiya,Masutaka Furue,Gaku Tsuji,Makiko Kido-Nakahara,Takeshi Nakahara

doi:10.3390/ijms20133324

Dugarmaa Ulzii, Kazuhisa Furue + Show 5 more

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https://doi.org/10.3390/ijms20133324

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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-4Rα/IL-13Rα1 and IL-13Rα2. The former one transduces a functional IL-13 signal, whereas the latter IL-13Rα2 works as a nonfunctional decoy receptor. To examine whether scratch injury affects the expression of IL-4Rα, IL-13Rα1, and IL-13Rα2, 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-13Rα2 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-13Rα2-overexpressed keratinocytes, confirming the decoy function of IL-13Rα2. Our findings indicate that scratching upregulates the expression of the IL-13 decoy receptor IL-13Rα2 and counteracts IL-13 signaling.

Highlights

Atopic dermatitis (AD) is a common, chronic or chronically relapsing, severely pruritic, eczematous skin disease that markedly deteriorates the quality of life of afflicted patients [1,2,3,4]
Itchiness is a specialized perception in the skin and an unpleasant sensation that elicits the desire to scratch in order to remove harmful stimuli, leading to a scratching behavior [25]
Among cutaneous inflammatory skin diseases, the vicious itch–scratch cycle is important in AD because it profoundly impairs the quality of life, treatment satisfaction and adherence, and socioeconomic stability of patients [28,29,30]

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Introduction

Atopic dermatitis (AD) is a common, chronic or chronically relapsing, severely pruritic, eczematous skin disease that markedly deteriorates the quality of life of afflicted patients [1,2,3,4]. Lifetime prevalence of AD is estimated to be as high as 20% in the general population [5,6]. Clinical symptoms and signs of AD are characterized by skin inflammation, barrier dysfunction (xerosis), and itching [1,7]. Severe and chronic pruritus induces unavoidable scratching, and the vicious itch–scratch cycle exacerbates and perpetuates atopic inflammation and skin barrier function [8,9]. Compounding evidence shows that acute AD lesions have a significantly greater number of T helper 2 (TH2) cells expressing interleukin-4 (IL-4) and IL-13 than normal skin or uninvolved AD skin [10]. The TH2-deviated immune response is demonstrated both in pediatric and adult AD [11,12]

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