miRNA-146a 抑制白细胞介素-17 介导的皮肤炎症，与银屑病具有遗传相关性。
MicroRNA-146a suppresses IL-17-mediated skin inflammation and is genetically associated with psoriasis.
机构信息
Dermatology and Venerology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
Dermatology and Venerology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Unit of Dermatology, Karolinska University Hospital, Stockholm, Sweden.
出版信息
J Allergy Clin Immunol. 2017 Feb;139(2):550-561. doi: 10.1016/j.jaci.2016.07.025. Epub 2016 Aug 24.
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.
背景
银屑病是一种具有强烈遗传背景的免疫介导性炎症性皮肤病，其中白细胞介素-17（IL-17）信号的激活在发病机制中起核心作用。关于非编码 RNA（包括 microRNA，miRNA）在疾病易感性中的作用，人们知之甚少。
目的
我们旨在研究 microRNA-146a（miR-146a）中单核苷酸多态性与银屑病的遗传相关性，并探讨其在疾病起始和缓解中的作用。
方法
对 1546 例银屑病患者和 1526 例对照者进行 miR-146a rs2910164 与银屑病的遗传相关性分析。采用 miR-146a 敲除小鼠结合咪喹莫特诱导的银屑病小鼠模型，评估 miR-146a 在银屑病患者中的作用。在形态学、组织学和分子水平上评估银屑病样皮肤炎症的严重程度。用白细胞介素-17（IL-17）处理角质形成细胞，过表达和抑制 miR-146a。将合成的 miR-146a 注射到小鼠真皮内。
结果
本研究报道了 miR-146a 前体（rs2910164）的功能性多态性与疾病保护性相关。miR-146a 基因缺失导致皮肤炎症更早发生且更严重，角质形成细胞来源的炎症介质、表皮过度增殖和中性粒细胞浸润增加，IL-17 诱导的表达增加。此外，在停止咪喹莫特刺激后，miR-146a 缺陷型小鼠的炎症无法缓解。miR-146a 的过表达抑制了，而其抑制增强了角质形成细胞中 IL-17 驱动的炎症。功能上，miR-146a 损害了角质形成细胞的中性粒细胞趋化能力。最后，将 miR-146a 模拟物递送至皮肤可改善银屑病样皮肤炎症，减少表皮增殖和中性粒细胞浸润。
结论
我们的研究结果定义了 miR-146a 在调节皮肤中 IL-17 驱动的炎症中的关键作用。
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