The Long Noncoding RNA DNM3OS Is a Reservoir of FibromiRs with Major Functions in Lung Fibroblast Response to TGF-β and Pulmonary Fibrosis
The Long Noncoding RNA DNM3OS Is a Reservoir of FibromiRs with Major Functions in Lung Fibroblast Response to TGF-β and Pulmonary Fibrosis
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DOI：
10.1164/rccm.201807-1237oc
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发表时间：
2019-07-15
影响因子：
24.7
通讯作者：
Pottier, Nicolas
中科院分区：
文献类型：
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作者：
Savary, Gregoire;Dewaeles, Edmone;Pottier, Nicolas
理由：鉴于特发性肺纤维化（IPF）缺乏有效的治疗方法，对控制肺成纤维细胞活化（驱动纤维形成过程的关键细胞类型）的有害机制的新见解对于开发新的治疗策略至关重要。 TGF-β（转化生长因子-β）是主要的促纤维化因子，但由于其多效性作用，其抑制与严重的副作用相关。目的：确定成纤维细胞中 TGF-β 的下游非编码效应子是否可能代表新的有效治疗靶点，其调节可能具有良好的耐受性。方法：我们研究了 TGF-β 刺激的肺成纤维细胞转录组的整个非编码部分，以确定肺成纤维细胞分化为新的基因组决定因素。肌成纤维细胞。长非编码 RNA (lncRNA) DNM3OS（动力 3 相对链）及其相关 microRNA (miRNA) 的差异表达在小鼠肺纤维化模型和 IPF 组织样本中得到验证。使用旨在干扰 DNM3OS 的独特且互补的反义寡核苷酸策略来阐明 DNM3OS 及其相关 miRNA 在 IPF 发病机制中的作用。测量和主要结果：我们确定 DNM3OS 是 TGF-β 诱导的肺肌成纤维细胞活化的成纤维细胞特异性关键下游效应器。从机制上讲，DNM3OS 通过产生三种不同的促纤维化成熟 miRNA（即 miR-199a-5p/3p 和 miR-214-3p）反式调节这一过程，从而以多方面的方式影响 TGF-β 信号传导的 SMAD 和非 SMAD 成分。在体内，我们发现干扰 DNM3OS 功能不仅可以预防肺纤维化，还可以改善已形成的肺纤维化。结论：旨在干扰 lncRNA DNM3OS 的药理学方法可能代表 IPF 的新有效治疗策略。
Rationale: Given the paucity of effective treatments for idiopathic pulmonary fibrosis (IPF), new insights into the deleterious mechanisms controlling lung fibroblast activation, the key cell type driving the fibrogenic process, are essential to develop new therapeutic strategies. TGF-beta (transforming growth factor-beta) is the main profibrotic factor, but its inhibition is associated with severe side effects because of its pleiotropic role.Objectives: To determine if downstream noncoding effectors of TGF-beta in fibroblasts may represent new effective therapeutic targets whose modulation may be well tolerated.Methods: We investigated the whole noncoding fraction of TGF-beta-stimulated lung fibroblast transcriptome to identify new genomic determinants of lung fibroblast differentiation into myofibroblasts. Differential expression of the long noncoding RNA (lncRNA) DNM3OS (dynamin 3 opposite strand) and its associated microRNAs (miRNAs) was validated in a murine model of pulmonary fibrosis and in IPF tissue samples. Distinct and complementary antisense oligonudeotide-based strategies aiming at interfering with DNM3OS were used to elucidate the role of DNM3OS and its associated miRNAs in IPF pathogenesis.Measurements and Main Results: We identified DNM3OS as a fibroblast-specific critical downstream effector of TGF-beta-induced lung myofibroblast activation. Mechanistically, DNM3OS regulates this process in trans by giving rise to three distinct profibrotic mature miRNAs (i.e., miR- 199a-5p/3p and miR-214-3p), which influence SMAD and non-SMAD components of TGF-beta signaling in a multifaceted way. In vivo, we showed that interfering with DNM3OS function not only prevents lung fibrosis but also improves established pulmonary fibrosis.Conclusions: Pharmacological approaches aiming at interfering with the lncRNA DNM3OS may represent new effective therapeutic strategies in IPF.