Counterregulation between thymic stromal lymphopoietin- and IL-23-driven immune axes shapes skin inflammation in mice with epidermal barrier defects

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:138

Article

Li, Jiagui¹  Leyva-Castillo, Juan Manuel^1,6,7  Hener, Pierre¹  Eisenmann, Aurelie¹  Zaafouri, Sarra²  Jonca, Nathalie²  Serre, Guy²  Birling, Marie-Christine³  Li, Mei^1,4,5 

[1] Univ Strasbourg, CNRS UMR7104, INSERM U964, Inst Genet & Biol Mol & Cellulaire, Illkirch Graffenstaden, France

[2] Univ Toulouse 3, CNRS UMR 165, INSERM U1056, Differenciat Epiderm & Autoimmun Rhumatoide, Toulouse, France

[3] Inst Clin Souris, Illkirch Graffenstaden, France

[4] Univ Strasbourg, Inst Adv Study, Strasbourg, France

[5] Freiburg Inst Adv Studies, Freiburg, Germany

[6] Harvard Med Sch, Childrens Hosp, Div Immunol, Boston, MA USA

[7] Harvard Med Sch, Dept Pediat, Boston, MA USA

关键词: Epidermal barrier;    corneodesmosin;    atopic dermatitis;    peeling skin syndrome type B;    thymic stromal lymphopoietin;    IL-23;    T(H)2;    T(H)17;    IL-1 beta;    skin inflammation;    mouse model;   

DOI  :  10.1016/j.jaci.2016.01.013

来源: Elsevier

【 摘 要 】

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-1 beta 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.

【 授权许可】

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