MicroRNA-146a Suppresses IL-17-mediated Skin Inflammation and Is Genetically Associated With Psoriasis

J Allergy Clin Immunol. 2017 Feb;139(2):550-561. doi: 10.1016/j.jaci.2016.07.025. Epub 2016 Aug 24.

Abstract

Background: 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.

Objective: 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.

Methods: 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.

Results: 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.

Conclusions: Our results define a crucial role for miR-146a in modulating IL-17-driven inflammation in the skin.

Keywords: IL-17; Psoriasis; keratinocyte; miR-146a; microRNA; mouse model; single nucleotide polymorphisms; skin inflammation.

MeSH terms

  • Adult
  • Aminoquinolines
  • Animals
  • Cell Proliferation
  • Cells, Cultured
  • Disease Models, Animal
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Humans
  • Imiquimod
  • Interleukin-17 / metabolism
  • Keratinocytes / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • MicroRNAs / administration & dosage
  • MicroRNAs / genetics*
  • Neutrophil Infiltration
  • Polymorphism, Single Nucleotide
  • Psoriasis / chemically induced
  • Psoriasis / genetics*
  • Psoriasis / immunology
  • Skin / immunology*
  • Sweden

Substances

  • Aminoquinolines
  • Interleukin-17
  • MIRN146 microRNA, human
  • MicroRNAs
  • Mirn146 microRNA, mouse
  • Imiquimod