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J Allergy Clin Immunol. 2014 Oct;134(4):836-847.e11. doi: 10.1016/j.jaci.2014.05.022. Epub 2014 Jul 2.

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

Author information

1
Swiss Institute of Allergy and Asthma Research (SIAF), University of Zürich, Davos, Switzerland; Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia. Electronic address: ana.rebane@ut.ee.
2
Swiss Institute of Allergy and Asthma Research (SIAF), University of Zürich, Davos, Switzerland; Institute of Molecular and Cellular Biology, University of Tartu, Tartu, Estonia.
3
Swiss Institute of Allergy and Asthma Research (SIAF), University of Zürich, Davos, Switzerland; Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
4
Swiss Institute of Allergy and Asthma Research (SIAF), University of Zürich, Davos, Switzerland.
5
Transgenic Technology Core Laboratory, University of Tartu, Tartu, Estonia.
6
Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
7
Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary; Dermatological Research Group of the Hungarian Academy of Sciences, Szeged, Hungary.
8
Department of Pathology, Tartu University Hospital, Tartu, Estonia.
9
Department of Dermatology and Venereology, University of Tartu, Tartu, Estonia; Dermatology Clinic, Tartu University Hospital, Tartu, Estonia.
10
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale/Université de Strasbourg, Illkirch, France.
11
Department of Molecular and Cellular Biology, Beckman Research Institute, City of Hope, Duarte, Calif.

Abstract

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.

KEYWORDS:

Allergy; atopic eczema; gene therapy; noncoding RNA

PMID:
24996260
DOI:
10.1016/j.jaci.2014.05.022
[Indexed for MEDLINE]

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