Counterregulation between thymic stromal lymphopoietin– and IL-23–driven immune axes shapes skin inflammation in mice with epidermal barrier defects - 01/07/16
Abstract |
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 Cdsniep−/− 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 Cdsniep−/− 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.
Le texte complet de cet article est disponible en PDF.Key words : Epidermal barrier, corneodesmosin, atopic dermatitis, peeling skin syndrome type B, thymic stromal lymphopoietin, IL-23, TH2, TH17, IL-1β, skin inflammation, mouse model
Abbreviations used : AD, ADAM17, CDSN, FLG, IHC, MBP, MCPT8, NS, PAR2, PSS-B, SC, TSLP, wka
Plan
| Supported by l'Agence Nationale de la Recherche (grant nos. ANR-13-BSV1-0024 and ANR-15-CE14-0009), Fondation Simone et Cino Del Duca (Institut de France), the Joint Programme of the Freiburg Institute for Advanced Studies (FRIAS) and the University of Strasbourg Institute for Advanced Study (USIAS), Société Française d'Allergologie (SFA), the Association pour la Recherche à l'IGBMC, the Centre National de la Recherche Scientifique (CNRS), the Institut National de la Santé et de la Recherche Médicale (INSERM), and the Université de Strasbourg (Unistra). |
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| Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. |
Vol 138 - N° 1
P. 150 - juillet 2016 Retour au numéro
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