MicroRNA-146a alleviates chronic skin inflammation in atopic dermatitis through suppression of innate immune responses in keratinocytes - 02/10/14
, Toomas Runnel, MSc a, c, Alar Aab, MSc a, b, Julia Maslovskaja, MSc a, b, Beate Rückert, BSc a, Maya Zimmermann, PhD a, Mario Plaas, PhD d, Jaanika Kärner, MSc a, b, Angela Treis, MSc a, Maire Pihlap, BSc b, Uku Haljasorg, MSc b, Helen Hermann, BSc b, Nikoletta Nagy, MD, PhD e, f, Lajos Kemeny, MD e, f, Triin Erm, MD g, Külli Kingo, MD, PhD h, i, Mei Li, PhD j, Mark P. Boldin, PhD k, Cezmi A. Akdis, MD aAbstract |
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-γ–inducible and AD-associated genes CCL5, CCL8, and ubiquitin D (UBD) in human primary keratinocytes stimulated with IFN-γ, TNF-α, or IL-1β. 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-γ, CCL5, CCL8, and UBD in the skin, and IFN-γ, IL-1β, 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.
Le texte complet de cet article est disponible en PDF.Key words : Allergy, noncoding RNA, atopic eczema, gene therapy
Abbreviations used : AD, CARD10, IRAK1, LN, miRNA, NF-κB, siRNA, STAT, TSLP, TLR, UBD, 3′UTR, WT
Plan
| This work was supported by the Swiss National Science Foundation (grant no. 32-132899 and grant no. 32-112306), the Christine Kühne-Center for Allergy Research and Education, Davos, Switzerland (CK-CARE), Swiss-Polish contribution, the Estonian Science Foundation (grant no. ESF8350 and grant no. ESF7437), European Regional Fund with Archimedes Foundation, European Union structural assistance grant (grant no. SARMP12219T), institutional research grant (grant no. IUT2-2), and personal research grants (grant no. PUT214 and grant no. PUT177) from the Estonian Research Council. A. Rebane was supported by fellowships from the SCIEX Program NMS-CH and ESTBIOREG. |
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| Disclosure of potential conflict of interest: M. Zimmermann has received research support from SNF. M. P. Boldin is employed by City of Hope, has received research support from the Tim Nesvig Lymphoma Foundation, and has stock/stock options in Regulus Therapeutics. C. A. Akdis has received research support from Novartis, PREDICTA, the Swiss National Science Foundation, Mechanisms of the Development of ALLergy, the Christine Kühne Center for Allergy Research and Education (CK-CARE), and Swiss-Polish Research Cooperation; has received consultancy fees from Actelion, Aventis, Stallergenes, Allergopharma, Circasia, and Anergis; and is employed by the Swiss Institute of Allergy and Asthma Research. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 134 - N° 4
P. 836 - octobre 2014 Retour au numéro
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