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

MicroRNA-146a suppresses IL-17-mediated skin inflammation and is genetically associated with psoriasis.

Author information

1
Dermatology and Venerology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
2
Dermatology and Venerology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Unit of Dermatology, Karolinska University Hospital, Stockholm, Sweden.
3
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.

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

PMID:
27568078
DOI:
10.1016/j.jaci.2016.07.025
[Indexed for MEDLINE]

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