Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji 133002, PR China; Department of Anatomy, Histology and Embryology, Yanbian University Medical College, Yanji 133002, PR China.
Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji 133002, PR China; Center of Medical Functional Experiment, Yanbian University Medical College, Yanji 133002, PR China.
Int Immunopharmacol. 2024 Mar 30;130:111703. doi: 10.1016/j.intimp.2024.111703. Epub 2024 Feb 28.
Bronchial asthma is known for airway inflammation, hyperresponsiveness, and remodeling.MicroRNAs (MiRNAs) have been involved in the development of asthma, whereas, the mechanism of various MiRNAs in asthma remains to be elucidated. In this study, we aim to explore the mechanism of miR-128-3p in asthma-related airway inflammation by targeting sine oculis homeobox homolog 1 (SIX1) to regulate the mitochondrial function. In an ovalbumin (OVA) asthma mouse model, miR-128-3p levels were found to be significantly diminished. Administration of miR-128-3p agomir decreased peribronchial inflammatory cell infiltration and improved airway inflammation. Afterwards, we used the luciferase reporter assay to predict and confirmed that SIX1 is a target gene of miR-128-3p. Overexpression of miR-128-3p attenuated IL-13-induced cellular inflammation and ROS production in bronchial epithelial cells (BEAS-2B). In vitro, overexpression of miR-128-3p and SIX1 knockdown mitigated mitochondrial fragmentation, reduced Drp1-mediated mitochondrial division, and upregulated mitochondrial membrane potential. Moreover, led to decreased production of ROS/mitochondrial ROS, P-Drp1(616) and Fis1 expression, while enhancing P-Drp1(637), MFN1, caspase-3/9, and Bax-mediated apoptosis. Our findings demonstrated that miR-128-3p could alleviate airway inflammation by downregulating SIX1 and improving mitochondrial function, positioning the miR-128-3p/SIX1/Drp1 signaling as a potential therapeutic target for asthma.
支气管哮喘以气道炎症、高反应性和重塑为特征。微小 RNA（miRNAs）参与哮喘的发生发展，然而，各种 miRNAs 在哮喘中的作用机制仍有待阐明。在本研究中，我们旨在通过靶向 sine oculis homeobox homolog 1（SIX1）来调节线粒体功能，探讨 miR-128-3p 在哮喘相关气道炎症中的作用机制。在卵清蛋白（OVA）哮喘小鼠模型中，发现 miR-128-3p 水平显著降低。给予 miR-128-3p agomir 可减少细支气管周围炎症细胞浸润并改善气道炎症。随后，我们使用荧光素酶报告基因检测预测并证实 SIX1 是 miR-128-3p 的靶基因。过表达 miR-128-3p 可减轻 IL-13 诱导的支气管上皮细胞（BEAS-2B）的细胞炎症和 ROS 产生。在体外，过表达 miR-128-3p 和敲低 SIX1 可减轻线粒体片段化，减少 Drp1 介导的线粒体分裂，并上调线粒体膜电位。此外，还可减少 ROS/线粒体 ROS、P-Drp1（616）和 Fis1 的表达，同时增强 P-Drp1（637）、MFN1、caspase-3/9 和 Bax 介导的凋亡。我们的研究结果表明，miR-128-3p 通过下调 SIX1 和改善线粒体功能来减轻气道炎症，提示 miR-128-3p/SIX1/Drp1 信号通路可能成为哮喘的潜在治疗靶点。
