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Background

Epidermal barrier dysfunction has been recognized as a critical factor in the initiation and exacerbation of skin inflammation, particularly in patients with atopic dermatitis (AD) and AD-like congenital disorders, including peeling skin syndrome type B. However, inflammatory responses developed in barrier-defective skin, as well as the underlying mechanisms, remained incompletely understood.

Objective

We aimed to decipher inflammatory axes and the cytokine network in mouse skin on breakdown of epidermal stratum corneum barrier.

Methods

We generated Cdsn(iep-/-) mice with corneodesmosin ablation in keratinocytes selectively in an inducible manner. We characterized inflammatory responses and cytokine expression by using histology, immunohistochemistry, ELISA, and quantitative PCR. We combined mouse genetic tools, antibody-mediated neutralization, signal-blocking reagents, and topical antibiotic treatment to explore the inflammatory axes.

Results

We show that on breakdown of the epidermal stratum corneum barrier, type 2 and type 17 inflammatory responses are developed simultaneously, driven by thymic stromal lymphopoietin (TSLP) and IL-23, respectively. Importantly, we reveal a counterregulation between these 2 inflammatory axes. Furthermore, we show that protease-activated receptor 2 signaling is involved in mediating the TSLP/type 2 axis, whereas skin bacteria are engaged in induction of the IL-23/type 17 axis. Moreover, we find that IL-1β is induced in skin of Cdsn(iep-/-) mice and that blockade of IL-1 signaling suppresses both TSLP and IL-23 expression and ameliorates skin inflammation.

Conclusion

The inflammatory phenotype in barrier-defective skin is shaped by counterregulation between the TSLP/type 2 and IL-23/type 17 axes. Targeting IL-1 signaling could be a promising therapeutic option for controlling skin inflammation in patients with peeling skin syndrome type B and other diseases related to epidermal barrier dysfunction, including AD."xsd:string
http://purl.uniprot.org/citations/26993035http://purl.org/dc/terms/identifier"doi:10.1016/j.jaci.2016.01.013"xsd:string
http://purl.uniprot.org/citations/26993035http://purl.uniprot.org/core/author"Li J."xsd:string
http://purl.uniprot.org/citations/26993035http://purl.uniprot.org/core/author"Li M."xsd:string
http://purl.uniprot.org/citations/26993035http://purl.uniprot.org/core/author"Jonca N."xsd:string
http://purl.uniprot.org/citations/26993035http://purl.uniprot.org/core/author"Serre G."xsd:string
http://purl.uniprot.org/citations/26993035http://purl.uniprot.org/core/author"Birling M.C."xsd:string
http://purl.uniprot.org/citations/26993035http://purl.uniprot.org/core/author"Eisenmann A."xsd:string
http://purl.uniprot.org/citations/26993035http://purl.uniprot.org/core/author"Hener P."xsd:string
http://purl.uniprot.org/citations/26993035http://purl.uniprot.org/core/author"Leyva-Castillo J.M."xsd:string
http://purl.uniprot.org/citations/26993035http://purl.uniprot.org/core/author"Zaafouri S."xsd:string
http://purl.uniprot.org/citations/26993035http://purl.uniprot.org/core/date"2016"xsd:gYear
http://purl.uniprot.org/citations/26993035http://purl.uniprot.org/core/name"J Allergy Clin Immunol"xsd:string
http://purl.uniprot.org/citations/26993035http://purl.uniprot.org/core/pages"150-161.e13"xsd:string
http://purl.uniprot.org/citations/26993035http://purl.uniprot.org/core/title"Counterregulation between thymic stromal lymphopoietin- and IL-23-driven immune axes shapes skin inflammation in mice with epidermal barrier defects."xsd:string
http://purl.uniprot.org/citations/26993035http://purl.uniprot.org/core/volume"138"xsd:string
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