TY - JOUR

T1 - MicroRNA-146a alleviates chronic skin inflammation in atopic dermatitis through suppression of innate immune responses in keratinocytes

AU - Rebane, Ana

AU - Runnel, Toomas

AU - Aab, Alar

AU - Maslovskaja, Julia

AU - Rückert, Beate

AU - Zimmermann, Maya

AU - Plaas, Mario

AU - Kärner, Jaanika

AU - Treis, Angela

AU - Pihlap, Maire

AU - Haljasorg, Uku

AU - Hermann, Helen

AU - Nagy, Nikoletta

AU - Kemeny, Lajos

AU - Erm, Triin

AU - Kingo, Külli

AU - Li, Mei

AU - Boldin, Mark P.

AU - Akdis, Cezmi A.

N1 - Funding Information: 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 . Funding Information: 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. Publisher Copyright: © 2014 American Academy of Allergy, Asthma and Immunology. 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.

PY - 2014/10/1

Y1 - 2014/10/1

N2 - 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.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-γinducible and ADassociated 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-146adeficient 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-146amediated suppression in allergic skin inflammation partially occurs through direct targeting of upstream nuclear factor kappa B signal transducers caspase recruitment domain- ontaining protein 10 and IL-1 receptorassociated 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 Bdependent inflammatory responses in keratinocytes and chronic skin inflammation in AD.

AB - 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.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-γinducible and ADassociated 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-146adeficient 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-146amediated suppression in allergic skin inflammation partially occurs through direct targeting of upstream nuclear factor kappa B signal transducers caspase recruitment domain- ontaining protein 10 and IL-1 receptorassociated 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 Bdependent inflammatory responses in keratinocytes and chronic skin inflammation in AD.

KW - Allergy

KW - atopic eczema

KW - gene therapy

KW - noncoding RNA

UR - http://www.scopus.com/inward/record.url?scp=84908123687&partnerID=8YFLogxK

U2 - 10.1016/j.jaci.2014.05.022

DO - 10.1016/j.jaci.2014.05.022

M3 - Journal article

C2 - 24996260

AN - SCOPUS:84908123687

VL - 134

SP - 836-847.e11

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

SN - 0091-6749

IS - 4

ER -