title: MicroRNA-146a suppresses IL-17-mediated skin inflammation and is genetically associated with psoriasis.
abstract: Psoriasis is an immune-mediated inflammatory skin disease with a strong genetic background in which activation of IL-17 signaling is central in the pathogenesis. Little has been known about the role of noncoding RNAs, including microRNAs (miRNAs), in predisposition to the disease.
  
  
  
  We sought to investigate the genetic association of single nucleotide polymorphisms in microRNA-146a (miR-146a) to psoriasis and to explore its function in the initiation and resolution of the disease.
  
  
  
  Analysis of the genetic association of miR-146a rs2910164 and psoriasis was carried out on 1546 patients with psoriasis and 1526 control subjects. The role of miR-146a in patients with psoriasis was assessed by using miR-146a-/-mice in conjunction with the imiquimod-induced mouse model of psoriasis. The severity of psoriasis-like skin inflammation was evaluated at morphologic, histologic, and molecular levels. miR-146a was ectopically overexpressed and inhibited in keratinocytes treated with IL-17. Synthetic miR-146a was injected intradermally into mice.
  
  
  
  Here we report protective association of a functional polymorphism in the miR-146a precursor (rs2910164). Genetic deficiency in miR-146a leads to earlier onset and exacerbated pathology of skin inflammation, with increased expression of IL-17-induced keratinocyte-derived inflammatory mediators, epidermal hyperproliferation, and increased neutrophil infiltration. Moreover, miR-146a-deficient mice do not resolve inflammation after discontinuation of imiquimod challenge. The overexpression of miR-146a suppressed, whereas its inhibition enhanced, IL-17-driven inflammation in keratinocytes. Functionally, miR-146a impairs the neutrophil chemoattractant capacity of keratinocytes. Finally, delivery of miR-146a mimics into the skin leads to amelioration of psoriasiform skin inflammation, decreased epidermal proliferation, and neutrophil infiltration.
  
  
  
  Our results define a crucial role for miR-146a in modulating IL-17-driven inflammation in the skin.
authors: Dermatology and Venerology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors: Ankit
authors: A
authors: Srivastava
authors: Dermatology and Venerology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors: Pernilla
authors: P
authors: Nikamo
authors: Dermatology and Venerology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors: Warangkana
authors: W
authors: Lohcharoenkal
authors: Dermatology and Venerology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors: Dongqing
authors: D
authors: Li
authors: Dermatology and Venerology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors: Florian
authors: F
authors: Meisgen
authors: Dermatology and Venerology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors: Ning
authors: N
authors: Xu Landén
authors: Dermatology and Venerology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Unit of Dermatology, Karolinska University Hospital, Stockholm, Sweden.
authors: Mona
authors: M
authors: Ståhle
authors: Dermatology and Venerology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors: Andor
authors: A
authors: Pivarcsi
authors: Dermatology and Venerology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Unit of Dermatology, Karolinska University Hospital, Stockholm, Sweden. Electronic address: eniko.sonkoly@ki.se.
authors: Enikö
authors: E
authors: Sonkoly
mesh_terms: D000328:Adult; D000634:Aminoquinolines; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D000077271:Imiquimod; D020381:Interleukin-17 / Q000378:metabolism; D015603:Keratinocytes / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000008:administration & dosage / Q000235:genetics*; D020556:Neutrophil Infiltration; D020641:Polymorphism, Single Nucleotide; D011565:Psoriasis / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology; D012867:Skin / Q000276:immunology*; D013548:Sweden
chemical_list: D000634:Aminoquinolines; D020381:Interleukin-17; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; C534190:Mirn146 microRNA, mouse; D000077271:Imiquimod
keywords: IL-17; Psoriasis; keratinocyte; miR-146a; microRNA; mouse model; single nucleotide polymorphisms; skin inflammation