Department of Neurosurgery, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan, Hubei 430030, P.R. China; Department of Neurosurgery, First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, Xinjiang 832008, P.R. China.
Department of Neurosurgery, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan, Hubei 430030, P.R. China.
Mol Ther. 2023 May 3;31(5):1313-1331. doi: 10.1016/j.ymthe.2023.01.031. Epub 2023 Feb 3.
Astrocyte-microglial interaction plays a crucial role in brain injury-associated neuroinflammation. Our previous data illustrated that astrocytes secrete microRNA, leading to anti-inflammatory effects on microglia. Long non-coding RNAs participate in neuroinflammation regulation after traumatic brain injury. However, the effect of astrocytes on microglial phenotype via long non-coding RNAs and the underlying molecular mechanisms remain elusive. We used long non-coding RNA sequencing on murine astrocytes and found that exosomal long non-coding RNA 4933431K23Rik attenuated traumatic brain injury-induced microglial activation in vitro and in vivo and ameliorated cognitive function deficiency. Furthermore, microRNA and messenger RNA sequencing together with binding prediction illustrated that exosomal long non-coding RNA 4933431K23Rik up-regulates E2F7 and TFAP2C expression by sponging miR-10a-5p. Additionally, E2F7 and TFAP2C, as transcription factors, regulated microglial Smad7 expression. Using Cx3cr1-Smad7 overexpression of adeno-associated virus, microglia specifically overexpressed Smad7 in the attenuation of neuroinflammation, resulting in less cognitive deficiency after traumatic brain injury. Mechanically, overexpressed Smad7 physically binds to IκBα and inhibits its ubiquitination, preventing NF-κB signaling activation. The Smad7 activator asiaticoside alleviates neuroinflammation and protects neuronal function in traumatic brain injury mice. This study revealed that an exosomal long non-coding RNA from astrocytes attenuates microglial activation after traumatic brain injury by up-regulating Smad7, providing a potential therapeutic target.
星形胶质细胞-小胶质细胞相互作用在脑损伤相关的神经炎症中起着至关重要的作用。我们之前的数据表明，星形胶质细胞分泌 microRNA，对小胶质细胞产生抗炎作用。长非编码 RNA 参与创伤性脑损伤后的神经炎症调节。然而，星形胶质细胞通过长非编码 RNA 对小胶质细胞表型的影响及其潜在的分子机制仍不清楚。我们使用小鼠星形胶质细胞的长非编码 RNA 测序，发现外泌体长非编码 RNA 4933431K23Rik 在体外和体内减轻创伤性脑损伤诱导的小胶质细胞激活，并改善认知功能缺陷。此外，microRNA 和信使 RNA 测序以及结合预测表明，外泌体长非编码 RNA 4933431K23Rik 通过海绵吸附 miR-10a-5p 而上调 E2F7 和 TFAP2C 的表达。此外，作为转录因子的 E2F7 和 TFAP2C 调节小胶质细胞 Smad7 的表达。使用腺相关病毒的 Cx3cr1-Smad7 过表达，小胶质细胞特异性过表达 Smad7 可减轻神经炎症，从而减少创伤性脑损伤后的认知缺陷。从机制上讲，过表达的 Smad7 与 IκBα 物理结合并抑制其泛素化，从而阻止 NF-κB 信号的激活。Smad7 激活剂积雪草酸在创伤性脑损伤小鼠中减轻神经炎症并保护神经元功能。本研究揭示了星形胶质细胞来源的外泌体长非编码 RNA 通过上调 Smad7 减轻创伤性脑损伤后的小胶质细胞激活，为潜在的治疗靶点提供了依据。
