Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm 17176, Sweden.
J Immunol. 2013 Apr 15;190(8):4066-75. doi: 10.4049/jimmunol.1200728. Epub 2013 Mar 20.
MicroRNAs (miRNAs) are known to regulate most biological processes and have been found dysregulated in a variety of diseases, including multiple sclerosis (MS). In this study, we characterized miRNAs that associate with susceptibility to develop experimental autoimmune encephalomyelitis (EAE) in rats, a well-established animal model of MS. Using Illumina next-generation sequencing, we detected 544 miRNAs in the lymph nodes of EAE-susceptible Dark Agouti and EAE-resistant Piebald Virol Glaxo rats during immune activation. Forty-three miRNAs were found differentially expressed between the two strains, with 81% (35 out of 43) showing higher expression in the susceptible strain. Only 33% of tested miRNAs displayed differential expression in naive lymph nodes, suggesting that a majority of regulated miRNAs are EAE dependent. Further investigation of a selected six miRNAs indicates differences in cellular source and kinetics of expression. Several of the miRNAs, including miR-146a, miR-21, miR-181a, miR-223, and let-7, have previously been implicated in immune system regulation. Moreover, 77% (33 out of 43) of the miRNAs were associated with MS and other autoimmune diseases. Target genes likely regulated by the miRNAs were identified using computational predictions combined with whole-genome expression data. Differentially expressed miRNAs and their targets involve functions important for MS and EAE, such as immune cell migration through targeting genes like Cxcr3 and cellular maintenance and signaling by regulation of Prkcd and Stat1. In addition, we demonstrated that these three genes are direct targets of miR-181a. Our study highlights the impact of multiple miRNAs, displaying diverse kinetics and cellular sources, on development of pathogenic autoimmune inflammation.
MicroRNAs (miRNAs) 被认为调节大多数生物过程，并在多种疾病中发现失调，包括多发性硬化症 (MS)。在这项研究中，我们鉴定了与实验性自身免疫性脑脊髓炎 (EAE) 在大鼠中的易感性相关的 miRNAs，EAE 是 MS 的一种成熟的动物模型。使用 Illumina 下一代测序，我们在免疫激活期间检测到易感性 Dark Agouti 和 EAE 抗性 Piebald Virol Glaxo 大鼠的淋巴结中的 544 个 miRNAs。在两个品系之间发现 43 个 miRNAs 表达差异，其中 81%（35 个中的 35 个）在易感品系中表达较高。只有 33%的测试 miRNA 在幼稚淋巴结中显示差异表达，表明大多数调节 miRNA 是 EAE 依赖性的。对选定的六个 miRNAs 的进一步研究表明细胞来源和表达动力学的差异。包括 miR-146a、miR-21、miR-181a、miR-223 和 let-7 在内的几种 miRNA 先前被认为与免疫系统调节有关。此外，43 个 miRNAs 中的 77%（33 个中的 33 个）与 MS 和其他自身免疫性疾病有关。使用计算预测结合全基因组表达数据，鉴定了可能由 miRNA 调节的靶基因。差异表达的 miRNAs 及其靶基因涉及 MS 和 EAE 等疾病的重要功能，例如通过靶向 Cxcr3 等基因的免疫细胞迁移以及通过调节 Prkcd 和 Stat1 进行细胞维持和信号传递。此外，我们证明这三个基因是 miR-181a 的直接靶基因。我们的研究强调了多种 miRNA 的影响，这些 miRNA 表现出不同的动力学和细胞来源，对致病性自身免疫炎症的发展有重要作用。
