Long noncoding RNA Malat1 regulates differential activation of macrophages and response to lung injury
Long noncoding RNA Malat1 regulates differential activation of macrophages and response to lung injury
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DOI：
10.1172/jci.insight.124522
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发表时间：
2019-02-21
期刊：
影响因子：
8
通讯作者：
Liu, Gang
中科院分区：
文献类型：
--
作者：
Cui, Huachun;Banerjee, Sami;Liu, Gang
巨噬细胞激活，即经典 M1 和替代 M2，在许多病理生理过程中发挥着关键作用，例如炎症和组织损伤与修复。尽管巨噬细胞激活的调节已得到广泛研究，但人们对长非编码 RNA (lncRNA) 在这一事件中的作用知之甚少。在这项研究中，我们发现 lncRNA Malat1 表达在差异激活的巨噬细胞中受到明显调节，因为它在 LPS 处理的细胞中上调，而在 IL-4 处理的细胞中下调。 Malat1 敲低会减弱 LPS 诱导的 M1 巨噬细胞活化。相比之下，Malat1 敲除增强了 IL-4 激活的 M2 分化以及巨噬细胞促纤维化表型。从机制上讲，Malat1 敲低导致 Clec16a 表达减少，其沉默体现了 Malat1 对 M1 激活的调节作用。有趣的是，Malat1 敲低促进了线粒体丙酮酸载体 (MPC) 的 IL-4 诱导及其对葡萄糖衍生氧化磷酸化 (OxPhos) 的介导，这对于 Malat1 对 M2 分化和促纤维化表型的调节至关重要。此外，整体或条件性骨髓敲除 Malat1 的小鼠表现出 LPS 诱导的全身和肺部炎症和损伤的减少。相比之下，这些小鼠出现了更严重的博莱霉素诱导的肺纤维化，并伴有肺泡巨噬细胞显示增强的 M2 和促纤维化表型。总之，我们已经确定了 Malat1 在巨噬细胞极化调节中的一个之前未被认识到的作用。我们的数据表明 Malat1 参与与巨噬细胞异常激活相关的肺部发病机制。
Macrophage activation, i.e., classical M1 and the alternative M2, plays a critical role in many pathophysiological processes, such as inflammation and tissue injury and repair. Although the regulation of macrophage activation has been under extensive investigation, there is little knowledge about the role of long noncoding RNAs (lncRNAs) in this event. In this study, we found that lncRNA Malat1 expression is distinctly regulated in differentially activated macrophages in that it is upregulated in LPS-treated and downregulated in IL-4-treated cells. Malat1 knockdown attenuates LPS-induced M1 macrophage activation. In contrast, Malat1 knockdown enhanced IL-4-activated M2 differentiation as well as a macrophage profibrotic phenotype. Mechanistically, Malat1 knockdown led to decreased expression of Clec16a, silencing of which phenocopied the regulatory effect of Malat1 on M1 activation. Interestingly, Malat1 knockdown promoted IL-4 induction of mitochondrial pyruvate carriers (MPCs) and their mediation of glucose-derived oxidative phosphorylation (OxPhos), which was crucial to the Malat1 regulation of M2 differentiation and profibrotic phenotype. Furthermore, mice with either global or conditional myeloid knockout of Malat1 demonstrated diminished LPS-induced systemic and pulmonary inflammation and injury. In contrast, these mice developed more severe bleomycin-induced lung fibrosis, accompanied by alveolar macrophages displaying augmented M2 and profibrotic phenotypes. In summary, we have identified what we believe is a previously unrecognized role of Malat1 in the regulation of macrophage polarization. Our data demonstrate that Malat1 is involved in pulmonary pathogeneses in association with aberrant macrophage activation.