MicroRNA-146a alleviates chronic skin inflammation in atopic dermatitis through suppression of innate immune responses in keratinocytes

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:134

Article

Rebane, Ana^1,2  Runnel, Toomas^1,3  Aab, Alar^1,2  Maslovskaja, Julia^1,2  Rueckert, Beate¹  Zimmermann, Maya¹  Plaas, Mario⁴  Kaener, Jaanika^1,2  Treis, Angela¹  Pihlap, Maire²  Haljasorg, Uku²  Hermann, Helen²  Nagy, Nikoletta^5,6  Kemeny, Lajos^5,6  Erm, Triin⁷  Kingo, Kuelli^8,9  Li, Mei¹⁰  Boldin, Mark P.¹¹  Akdis, Cezmi A.¹ 

[1] Univ Zurich, Swiss Inst Allergy & Asthma Res SIAF, Davos, Switzerland

[2] Univ Tartu, Inst Biomed & Translat Med, EE-50411 Tartu, Estonia

[3] Univ Tartu, Inst Mol & Cellular Biol, EE-50411 Tartu, Estonia

[4] Univ Tartu, Transgen Technol Core Lab, EE-50411 Tartu, Estonia

[5] Univ Szeged, Dept Dermatol & Allergol, Szeged, Hungary

[6] Hungarian Acad Sci, Dermatol Res Grp, Szeged, Hungary

[7] Tartu Univ Hosp, Dept Pathol, Tartu, Estonia

[8] Univ Tartu, Dept Dermatol & Venereol, EE-50411 Tartu, Estonia

[9] Tartu Univ Hosp, Dermatol Clin, Tartu, Estonia

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

[11] City Hope Natl Med Ctr, Beckman Res Inst, Dept Mol & Cellular Biol, Duarte, CA 91010 USA

关键词: Allergy;    noncoding RNA;    atopic eczema;    gene therapy;   

DOI  :  10.1016/j.jaci.2014.05.022

来源: Elsevier

【 摘 要 】

Background: Chronic skin inflammation in atopic dermatitis (AD) is associated with elevated expression of proinflammatory genes and activation of innate immune responses in keratinocytes. microRNAs (miRNAs) are short, single-stranded RNA molecules that silence genes via the degradation of target mRNAs or inhibition of translation. Objective: The aim of this study was to investigate the role of miR-146a in skin inflammation in AD. Methods: RNA and protein expression was analyzed using miRNA and mRNA arrays, RT-quantitative PCR, Western blotting, and immunonohistochemistry. Transfection of miR-146a precursors and inhibitors into human primary keratinocytes, luciferase assays, and MC903-dependent mouse model of AD were used to study miR-146a function. Results: We show that miR-146a expression is increased in keratinocytes and chronic lesional skin of patients with AD. miR-146a inhibited the expression of numerous proinflammatory factors, including IFN-gamma-inducible and AD-associated genes CCL5, CCL8, and ubiquitin D (UBD) in human primary keratinocytes stimulated with IFN-gamma, TNF-alpha, or IL-1 beta. In a mouse model of AD, miR-146a-deficient mice developed stronger inflammation characterized by increased accumulation of infiltrating cells in the dermis, elevated expression of IFN-gamma, CCL5, CCL8, and UBD in the skin, and IFN-gamma, IL-1 beta, and UBD in draining lymph nodes. Both tissue culture and in vivo experiments in mice demonstrated that miR-146a-mediated suppression in allergic skin inflammation partially occurs through direct targeting of upstream nuclear factor kappa B signal transducers caspase recruitment domain-containing protein 10 and IL-1 receptor-associated kinase 1. In addition, human CCL5 was determined as a novel, direct target of miR-146a. Conclusion: Our data demonstrate that miR-146a controls nuclear factor kappa B-dependent inflammatory responses in keratinocytes and chronic skin inflammation in AD.

【 授权许可】

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