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

Ana Rebane, Toomas Runnel, Alar Aab, Julia Maslovskaja, Beate Rückert, Maya Zimmermann, Mario Plaas, Jaanika Kärner, Angela Treis, Maire Pihlap, Uku Haljasorg, Helen Hermann, Nikoletta Nagy, Lajos Kemeny, Triin Erm, Külli Kingo, Mei Li, Mark P. Boldin, Cezmi A. Akdis

Research output: Contribution to journalArticle

83 Citations (Scopus)

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.

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.

Original languageEnglish
Pages (from-to)836-847.e11
JournalJournal of Allergy and Clinical Immunology
Volume134
Issue number4
DOIs
Publication statusPublished - Oct 1 2014

Keywords

  • Allergy
  • atopic eczema
  • gene therapy
  • noncoding RNA

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Rebane, A., Runnel, T., Aab, A., Maslovskaja, J., Rückert, B., Zimmermann, M., Plaas, M., Kärner, J., Treis, A., Pihlap, M., Haljasorg, U., Hermann, H., Nagy, N., Kemeny, L., Erm, T., Kingo, K., Li, M., Boldin, M. P., & Akdis, C. A. (2014). MicroRNA-146a alleviates chronic skin inflammation in atopic dermatitis through suppression of innate immune responses in keratinocytes. Journal of Allergy and Clinical Immunology, 134(4), 836-847.e11. https://doi.org/10.1016/j.jaci.2014.05.022