Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA.
School of Medicine, Tongji University, Shanghai, 200092, China.
J Neuroimmune Pharmacol. 2020 Sep;15(3):390-399. doi: 10.1007/s11481-019-09864-z. Epub 2019 Jul 20.
Long non-coding RNAs (lncRNAs), including long intergenic non-coding RNAs (lincRNAs), play an important regulatory role in controlling various biological processes. Both in vitro and in vivo studies have demonstrated that lincRNA-Cox2 plays a global regulatory role in regulating the expression of immune genes. Extracellular vesicles (EVs) are cell-derived nanosized membrane vesicles that have gained increasing attention in recent years due to their ability to efficiently deliver therapeutics to specific target organs or cell types. In this study, we found that lincRNA-Cox2 controls the expression of a set of cell cycle genes in lipopolysaccharide (LPS)-stimulated microglial cells. Our in vitro study suggested that knocking down lincRNA-Cox2 reversed LPS-induced microglial proliferation. In addition, our in vivo study demonstrated that intranasally delivered lincRNA-Cox2-siRNA loaded EVs could reach the brain resulting in a significant decrease in the expression of lincRNA-Cox2 in the microglia. Importantly, lincRNA-Cox2-siRNA loaded EVs also decreased LPS-induced microglial proliferation in mice. These findings indicate that intranasal delivery of EV-loaded small RNA could be developed as therapeutics for treatment of a multitude of CNS disorders.
长非编码 RNA（lncRNA），包括长基因间非编码 RNA（lincRNA），在控制各种生物过程中发挥着重要的调节作用。体外和体内研究都表明，lincRNA-Cox2 在调节免疫基因的表达方面具有全局调控作用。细胞外囊泡（EVs）是近年来受到越来越多关注的细胞来源的纳米尺寸膜囊泡，因为它们能够将治疗药物有效地递送到特定的靶器官或靶细胞类型。在本研究中，我们发现 lincRNA-Cox2 控制脂多糖（LPS）刺激的小神经胶质细胞中一组细胞周期基因的表达。我们的体外研究表明，敲低 lincRNA-Cox2 逆转了 LPS 诱导的小神经胶质细胞增殖。此外，我们的体内研究表明，经鼻腔递送的 lincRNA-Cox2-siRNA 负载的 EVs 可以到达大脑，导致小神经胶质细胞中 lincRNA-Cox2 的表达显著降低。重要的是，负载 lincRNA-Cox2-siRNA 的 EVs 还降低了 LPS 诱导的小鼠小神经胶质细胞增殖。这些发现表明，经鼻腔递送负载小 RNA 的 EV 可作为治疗多种中枢神经系统疾病的治疗方法。
