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

被引：167

作者：

Rebane, Ana ^{[1
,2
]}

Runnel, Toomas ^{[1
,3
]}

Aab, Alar ^{[1
,2
]}

Maslovskaja, Julia ^{[1
,2
]}

Rueckert, Beate ^{[1
]}

Zimmermann, Maya ^{[1
]}

Plaas, Mario ^{[4
]}

Kaener, Jaanika ^{[1
,2
]}

Treis, Angela ^{[1
]}

Pihlap, Maire ^{[2
]}

Haljasorg, Uku ^{[2
]}

Hermann, Helen ^{[2
]}

Nagy, Nikoletta ^{[5
,6
]}

Kemeny, Lajos ^{[5
,6
]}

Erm, Triin ^{[7
]}

Kingo, Kuelli ^{[8
,9
]}

Li, Mei ^{[10
]}

Boldin, Mark P. ^{[11
]}

Akdis, Cezmi A. ^{[1
]}

机构：

[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

来源：

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY | 2014年 / 134卷 / 04期

基金：

瑞士国家科学基金会;

关键词：

Allergy; noncoding RNA; atopic eczema; gene therapy; NF-KAPPA-B; THYMIC STROMAL LYMPHOPOIETIN; T-CELL; IFN-GAMMA; EPITHELIAL-CELLS; ECZEMATOUS DERMATITIS; SIGNALING PROTEINS; GENE-EXPRESSION; ACTIVATION; APOPTOSIS;

D O I：

10.1016/j.jaci.2014.05.022

中图分类号：

R392 [医学免疫学];

学科分类号：

100102 ;

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.

引用

页码：836 / U443

页数：23

共 64 条

[31] The cutaneous innate immune response in patients with atopic dermatitis [J].