Department of Pharmacy, Henan Provincial People's Hospital, Zhengzhou, 450000, Henan, China.
Department of Pharmacy, People's Hospital of Zhengzhou University, Zhengzhou University, No. 7 Weiwu Road, Zhengzhou, 450000, Henan, China.
Mol Neurobiol. 2024 Apr;61(4):2136-2150. doi: 10.1007/s12035-023-03664-6. Epub 2023 Oct 19.
Our previous studies have discovered that long non-coding RNA (lncRNA) MALAT1 and its target microRNA-125b-5p (miR-125b-5p) are implicated in neurological diseases via regulating neuroinflammation and neuronal injury. This study aimed to further explore the relationship between lncRNA MALAT1 and miR-125b-5p, as well as their effect on microglial activation, neuroinflammation, and neural apoptosis in spinal cord injury (SCI). Primary microglia from Sprague Dawley rats were stimulated with lipopolysaccharide (LPS). Then, microglia were transfected with lncRNA MALAT1 overexpression or knock-down adenovirus-associated virus with or without miR-125b-5p mimic. The culture medium of microglia was incubated with primary neurons. SCI rats were established for in vivo validation. LncRNA MALAT1 expression was reduced by LPS treatment in a dose-dependent manner. LncRNA MALAT1 overexpression suppressed the microglial M1 polarization (decreased iNOS but increased ARG1), neuroinflammation (declined PTGS2, TNF-α, IL-1β, and IL-6), and microglia-induced neural apoptosis (lower TUNEL positive cells and C-caspase3 but higher BCL2) under LPS treatment; its knock-down displayed the opposite trend. Moreover, lncRNA MALAT1 directly bound to and negatively regulated miR-125b-5p. MiR-125b-5p mimic promoted microglial M1 polarization, neuroinflammation, and microglia-induced neural apoptosis following LPS treatment; also, it could attenuate the effect of lncRNA MALAT1. Further in vivo study displayed that lncRNA MALAT1 overexpression elevated the Basso-Beattie-Bresnahan motor function score and improved neural injury. Also, in vivo validation indicated a similar effect of lncRNA MALAT1 on microglial polarization and neuroinflammation as in vitro. LncRNA MALAT1 improves SCI recovery via miR-125b-5p mediated microglial M1 polarization, neuroinflammation, and neural apoptosis.
我们之前的研究发现，长链非编码 RNA（lncRNA）MALAT1 及其靶 microRNA-125b-5p（miR-125b-5p）通过调节神经炎症和神经元损伤参与神经疾病。本研究旨在进一步探讨 lncRNA MALAT1 与 miR-125b-5p 之间的关系，以及它们对脊髓损伤（SCI）中小胶质细胞激活、神经炎症和神经凋亡的影响。用脂多糖（LPS）刺激 Sprague Dawley 大鼠原代小胶质细胞。然后，用 lncRNA MALAT1 过表达或敲低腺相关病毒转染小胶质细胞，并用或不用 miR-125b-5p 模拟物。将小胶质细胞的培养基与原代神经元孵育。建立 SCI 大鼠进行体内验证。LPS 处理呈剂量依赖性降低 lncRNA MALAT1 的表达。LncRNA MALAT1 过表达抑制 LPS 处理下小胶质细胞 M1 极化（降低 iNOS 但增加 ARG1）、神经炎症（下调 PTGS2、TNF-α、IL-1β 和 IL-6）和小胶质细胞诱导的神经凋亡（TUNEL 阳性细胞和 C-caspase3 减少，但 BCL2 增加）；其敲低则显示相反的趋势。此外，lncRNA MALAT1 直接结合并负调控 miR-125b-5p。miR-125b-5p 模拟物促进 LPS 处理后小胶质细胞 M1 极化、神经炎症和小胶质细胞诱导的神经凋亡；同时，它可以减弱 lncRNA MALAT1 的作用。进一步的体内研究显示，lncRNA MALAT1 过表达提高了 Basso-Beattie-Bresnahan 运动功能评分并改善了神经损伤。此外，体内验证表明，lncRNA MALAT1 对小胶质细胞极化和神经炎症的作用与体外相似。lncRNA MALAT1 通过 miR-125b-5p 介导的小胶质细胞 M1 极化、神经炎症和神经凋亡改善 SCI 恢复。
