BACKGROUND LCPUFAs are suggestive of having beneficial effects on inflammatory diseases such as asthma. However, little is known about the modulative capacity of omega-(n)-3 and n-6 LCPUFAs within the epigenetic regulation of inflammatory processes. OBJECTIVE The aim of this study was to investigate whether a specific combined LCPUFA supplementation restores disease-dysregulated miRNA-profiles in asthmatic mice. In addition, we determined the effect of the LCPUFA supplementation on the interaction of the most regulated miRNA expression and oxygenase activity in vitro. METHODS Sequencing of miRNA was performed by NGS from lung tissue of asthmatic and control mice with normal diet, as well as of LCPUFA supplemented asthmatic mice. Network analysis and evaluation of the biological targets of the miRNAs were performed by DIANA- miRPath v.3 webserver software, TargetScanMouse 7.2, and tool String v.10, respectively. Expression of hsa-miRNA-146a-5p and activity of COX-2 and 5-LO in LCPUFA-treated A549 cells were assessed by qPCR and flow cytometry, respectively. RESULTS In total, 62 miRNAs were dysregulated significantly in murine allergic asthma. The LCPUFA combination restored 21 of these dysregulated miRNAs, of which eight (mmu-miR-146a-5p, -30a-3p, -139-5p, -669p-5p, -145a-5p, -669a-5p, -342-3p and -15b-5p) were even normalized compared to the control levels. Interestingly, six of the eight rescued miRNAs are functionally implicated in TGF-β signaling, ECM-receptor interaction and fatty acid biosynthesis. Furthermore, in vitro experiments demonstrated that upregulation of hsa-miRNA-146a-5p is accompanied by a reduction of COX-2 and 5-LO activity. Moreover, transfection experiments revealed that LCPUFAs inhibit 5-LO activity in the presence and absence of anti-miR-146a-5p. CONCLUSION Our results demonstrate the modulative capacity of LCPUFAs on dysregulated miRNA expression in asthma. In addition, we pointed out the high regulative potential of LCPUFAs on 5-LO regulation and provided evidence that miR-146a partly controls the regulation of 5-LO.

中文翻译：

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LCPUFA的组合调节鼠哮喘模型和人肺泡细胞中miRNA-146a-5p的表达。

背景技术LCPUFA暗示对炎性疾病例如哮喘具有有益作用。然而，关于炎症过程的表观遗传调控中的ω-（n）-3和n-6 LCPUFAs的调节能力知之甚少。目的本研究的目的是研究特定的联合LCPUFA补充剂能否恢复哮喘小鼠中疾病失调的miRNA谱。此外，我们确定了LCPUFA补充剂对体外受调控最强的miRNA表达和加氧酶活性的相互作用的影响。方法采用NGS从正常饮食的哮喘和对照组小鼠以及补充LCPUFA的哮喘小鼠的肺组织中对miRNA进行测序。通过DIANAmiRPath v对miRNA的生物学靶标进行网络分析和评估。3个Web服务器软件，TargetScanMouse 7.2和工具String v.10。通过qPCR和流式细胞术分别评估了Lsafa处理的A549细胞中hsa-miRNA-146a-5p的表达以及COX-2和5-LO的活性。结果在鼠类过敏性哮喘中，总共有62个miRNA失调。LCPUFA组合可还原这些失调的miRNA中的21种，其中8种（mmu-miR-146a-5p，-30a-3p，-139-5p，-669p-5p，-145a-5p，-669a-5p，-342-与对照水平相比，甚至将3p和-15b-5p）标准化。有趣的是，八种挽救的miRNA中有六种在功能上涉及TGF-β信号传导，ECM-受体相互作用和脂肪酸生物合成。此外，体外实验表明，hsa-miRNA-146a-5p的上调伴随着COX-2和5-LO活性的降低。此外，转染实验表明，在存在和不存在抗miR-146a-5p的情况下，LCPUFAs均可抑制5-LO活性。结论我们的结果证明了LCPUFA对哮喘中miRNA表达失调的调节能力。此外，我们指出了LCPUFAs对5-LO调控的高调节潜力，并提供了证据表明miR-146a部分控制了5-LO的调控。