title: MicroRNA-146a alleviates chronic skin inflammation in atopic dermatitis through suppression of innate immune responses in keratinocytes.
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.
  
  
  CONCLUSIONS
  Our data demonstrate that miR-146a controls nuclear factor kappa B-dependent inflammatory responses in keratinocytes and chronic skin inflammation in AD.
authors.affiliation: 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.
authors.forename: Ana
authors.initials: A
authors.lastname: Rebane
authors.affiliation: Swiss Institute of Allergy and Asthma Research (SIAF), University of Zürich, Davos, Switzerland; Institute of Molecular and Cellular Biology, University of Tartu, Tartu, Estonia.
authors.forename: Toomas
authors.initials: T
authors.lastname: Runnel
authors.affiliation: Swiss Institute of Allergy and Asthma Research (SIAF), University of Zürich, Davos, Switzerland; Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
authors.forename: Alar
authors.initials: A
authors.lastname: Aab
authors.affiliation: Swiss Institute of Allergy and Asthma Research (SIAF), University of Zürich, Davos, Switzerland; Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
authors.forename: Julia
authors.initials: J
authors.lastname: Maslovskaja
authors.affiliation: Swiss Institute of Allergy and Asthma Research (SIAF), University of Zürich, Davos, Switzerland.
authors.forename: Beate
authors.initials: B
authors.lastname: Rückert
authors.affiliation: Swiss Institute of Allergy and Asthma Research (SIAF), University of Zürich, Davos, Switzerland.
authors.forename: Maya
authors.initials: M
authors.lastname: Zimmermann
authors.affiliation: Transgenic Technology Core Laboratory, University of Tartu, Tartu, Estonia.
authors.forename: Mario
authors.initials: M
authors.lastname: Plaas
authors.affiliation: Swiss Institute of Allergy and Asthma Research (SIAF), University of Zürich, Davos, Switzerland; Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
authors.forename: Jaanika
authors.initials: J
authors.lastname: Kärner
authors.affiliation: Swiss Institute of Allergy and Asthma Research (SIAF), University of Zürich, Davos, Switzerland.
authors.forename: Angela
authors.initials: A
authors.lastname: Treis
authors.affiliation: Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
authors.forename: Maire
authors.initials: M
authors.lastname: Pihlap
authors.affiliation: Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
authors.forename: Uku
authors.initials: U
authors.lastname: Haljasorg
authors.affiliation: Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
authors.forename: Helen
authors.initials: H
authors.lastname: Hermann
authors.affiliation: Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary; Dermatological Research Group of the Hungarian Academy of Sciences, Szeged, Hungary.
authors.forename: Nikoletta
authors.initials: N
authors.lastname: Nagy
authors.affiliation: Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary; Dermatological Research Group of the Hungarian Academy of Sciences, Szeged, Hungary.
authors.forename: Lajos
authors.initials: L
authors.lastname: Kemeny
authors.affiliation: Department of Pathology, Tartu University Hospital, Tartu, Estonia.
authors.forename: Triin
authors.initials: T
authors.lastname: Erm
authors.affiliation: Department of Dermatology and Venereology, University of Tartu, Tartu, Estonia; Dermatology Clinic, Tartu University Hospital, Tartu, Estonia.
authors.forename: Külli
authors.initials: K
authors.lastname: Kingo
authors.affiliation: 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.
authors.forename: Mei
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Molecular and Cellular Biology, Beckman Research Institute, City of Hope, Duarte, Calif.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Boldin
authors.affiliation: Swiss Institute of Allergy and Asthma Research (SIAF), University of Zürich, Davos, Switzerland.
authors.forename: Cezmi A
authors.initials: CA
authors.lastname: Akdis
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000008:administration & dosage / Q000031:analogs & derivatives; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D002908:Chronic Disease; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003876:Dermatitis, Atopic / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology; D004195:Disease Models, Animal; D006801:Humans; D007113:Immunity, Innate; D007165:Immunosuppression Therapy; D007249:Inflammation / Q000235:genetics; D018836:Inflammation Mediators / Q000378:metabolism; D015603:Keratinocytes / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics; D012867:Skin / Q000276:immunology* / Q000473:pathology; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; C055085:calcipotriene; D002117:Calcitriol
keywords: Allergy; atopic eczema; gene therapy; noncoding RNA