中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2022, Vol. 17 ›› Issue (5): 1096-1105.doi: 10.4103/1673-5374.322645

• 原著:退行性病与再生 • 上一篇    下一篇

HOXA11-AS可加重创伤性脑损伤后小胶质细胞诱导的神经炎症

  

  • 出版日期:2022-05-15 发布日期:2021-11-22

HOXA11-AS aggravates microglia-induced neuroinflammation after traumatic brain injury

Xiang-Long Li1, 2, 3, Bin Wang1, Fu-Bing Yang1, Li-Gang Chen1, 2, 3, *, Jian You1, 2, 3, *   

  1. 1Department of Neurosurgery, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, China; 2Neurosurgical Clinical Research Center and Academician (Expert) Workstation of Sichuan Province, Luzhou, Sichuan Province, China; 3Laboratory of Neurological Diseases and Brain Functions, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, China
  • Online:2022-05-15 Published:2021-11-22
  • Contact: Jian You, MD, dr_you00@163.com; Li-Gang Chen, ligangchen86@163.com.
  • Supported by:
    This study was supported by the Science and Technology Project of Sichuan Province of China, No. 2020YJ0188; and the Science and Technology Foundation of Luzhou of China, No. 2017LZXNYD-J10 (both to XLL).

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摘要：

长链非编码RNA可通过介导神经炎症和凋亡参与创伤性脑损伤后的多种病理生理过程。HOXA11-AS是lncRNA家族成员之一，有研究显示其可参与多种炎症反应，但其是否也在创伤性脑损伤中发挥作用尚不可知。为此，（1）实验建立自由落体打击创伤性脑损伤大鼠模型，并于造模前2周在脑室注射LV-HOXA11-AS。结果显示，HOXA11-AS过表达可加剧创伤性脑损伤大鼠神经功能缺损，增加脑含水量以及细胞凋亡，促进炎性因子白细胞介素1β、白细胞介素6和肿瘤坏死因子α的分泌，同时促进星形胶质细胞和小胶质细胞的活化；（2）以100 ng/mL脂多糖诱导小胶质细胞24h构建体外模型，以pcDNA-HOXA11-AS，miR-124-3p模拟物或sh-中期因子转染细胞。发现HOXA11-AS可抑制miR-124-3p表达，增强中期因子表达和TLR4-核因子κB通路的活化。此外，脂多糖可增强小胶质细胞诱导的星形胶质细胞的炎症反应。过表达miR-124-3p或下调中期因子则可抑制小胶质细胞的活化和星形胶质细胞的炎症反应。然而，miR-124-3p介导的抗炎作用能被HOXA11-AS过表达所逆转；（4）结果提示HOXA11-AS可通过调节miR-124-3p-中期因子轴加重创伤性脑损伤后神经炎症。实验于2019年2月4日经西南医科大学动物伦理委员会的批准（批准号SMU-2019-042）。

https://orcid.org/0000-0003-3979-3696 (Jian You)

关键词: 创伤性脑损伤, HOXA11-AS, miR-124-3p, 中期因子, 小胶质细胞, 星形胶质细胞, 神经炎症, 竞争性内源RNA

Abstract: Long noncoding RNAs (lncRNAs) participate in many pathophysiological processes after traumatic brain injury by mediating neuroinflammation and apoptosis. Homeobox A11 antisense RNA (HOXA11-AS) is a member of the lncRNA family that has been reported to participate in many inflammatory reactions; however, its role in traumatic brain injury remains unclear. In this study, we established rat models of traumatic brain injury using a weight-drop hitting device and injected LV-HOXA11-AS into the right lateral ventricle 2 weeks before modeling. The results revealed that overexpression of HOXA11-AS aggravated neurological deficits in traumatic brain injury rats, increased brain edema and apoptosis, promoted the secretion of proinflammatory factors interleukin-1β, interleukin-6, and tumor necrosis factor α, and promoted the activation of astrocytes and microglia. Microglia were treated with 100 ng/mL lipopolysaccharide for 24 hours to establish in vitro cell models, and then transfected with pcDNA-HOXA11-AS, miR-124-3p mimic, or sh-MDK. The results revealed that HOXA11-AS inhibited miR-124-3p expression and boosted MDK expression and TLR4-nuclear factor-κB pathway activation. Furthermore, lipopolysaccharide enhanced potent microglia-induced inflammatory responses in astrocytes. Forced overexpression of miR-124-3p or downregulating MDK repressed microglial activation and the inflammatory response of astrocytes. However, the miR-124-3p-mediated anti-inflammatory effects were reversed by HOXA11-AS. These findings suggest that HOXA11-AS can aggravate neuroinflammation after traumatic brain injury by modulating the miR-124-3p-MDK axis. This study was approved by the Animal Protection and Use Committee of Southwest Medical University (approval No. SMU-2019-042) on February 4, 2019. 

Key words: astrocyte, competitive endogenous RNA, HOXA11-AS, microglia, midkine, miR-124-3p, neuroinflammation, traumatic brain injury

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