Li Xiang-Long, Wang Bin, Yang Fu-Bing, Chen Li-Gang, You Jian
Department of Neurosurgery, the Affiliated Hospital of Southwest Medical University; Neurosurgical Clinical Research Center and Academician (Expert) Workstation of Sichuan Province; Laboratory of Neurological Diseases and Brain Functions, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, China.
Department of Neurosurgery, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, China.
Neural Regen Res. 2022 May;17(5):1096-1105. doi: 10.4103/1673-5374.322645.
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.
长链非编码RNA（lncRNAs）通过介导神经炎症和细胞凋亡参与创伤性脑损伤后的许多病理生理过程。同源框A11反义RNA（HOXA11-AS）是lncRNA家族的成员，据报道其参与许多炎症反应；然而，其在创伤性脑损伤中的作用仍不清楚。在本研究中，我们使用重物撞击装置建立了创伤性脑损伤大鼠模型，并在建模前2周将LV-HOXA11-AS注入右侧脑室。结果显示，HOXA11-AS的过表达加重了创伤性脑损伤大鼠的神经功能缺损，增加了脑水肿和细胞凋亡，促进了促炎因子白细胞介素-1β、白细胞介素-6和肿瘤坏死因子α的分泌，并促进了星形胶质细胞和小胶质细胞的激活。用100 ng/mL脂多糖处理小胶质细胞24小时以建立体外细胞模型，然后用pcDNA-HOXA11-AS、miR-124-3p模拟物或sh-MDK转染。结果显示，HOXA11-AS抑制miR-124-3p表达并增强MDK表达和TLR4-核因子-κB途径激活。此外，脂多糖增强了小胶质细胞诱导的星形胶质细胞炎症反应。miR-124-3p的强制过表达或MDK的下调抑制了小胶质细胞激活和星形胶质细胞的炎症反应。然而，HOXA11-AS逆转了miR-124-3p介导的抗炎作用。这些发现表明，HOXA11-AS可通过调节miR-124-3p-MDK轴加重创伤性脑损伤后的神经炎症。本研究于2019年2月4日获得西南医科大学动物保护与使用委员会批准（批准号SMU-2019-042）。
