星形胶质细胞衍生的富含 miR-873a-5p 的外泌体通过调节创伤性脑损伤后小胶质细胞表型抑制神经炎症。

Astrocyte-derived exosomes enriched with miR-873a-5p inhibit neuroinflammation via microglia phenotype modulation after traumatic brain injury.

机构信息

Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.

Department of Neurosurgery, First Affiliated Hospital of Medical College, Shihezi University, Shihezi, China.

出版信息

J Neuroinflammation. 2020 Mar 19;17(1):89. doi: 10.1186/s12974-020-01761-0.

DOI:10.1186/s12974-020-01761-0

PMID:32192523

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7082961/

Abstract

BACKGROUND

The interaction between astrocytes and microglia plays a vital role in the damage and repair of brain lesions due to traumatic brain injury (TBI). Recent studies have shown that exosomes act as potent mediators involved in intercellular communication.

METHODS

In the current study, the expression of inflammatory factors and miR-873a-5p in the lesion area and oedema area was evaluated in 15 patients with traumatic brain injury. Exosomes secreted by astrocytes were detected by immunofluorescence, Western blot and electron microscopy. A mouse model of TBI and an in vitro model of LPS-induced primary microglia were established to study the protective mechanism of exosomes from miR-873a-5p overexpressing in TBI-induced nerve injury.

RESULTS

We discovered that exosomes derived from activated astrocytes promote microglial M2 phenotype transformation following TBI. More than 100 miRNAs were detected in these astrocyte-derived exosomes. miR-873a-5p is a major component that was highly expressed in human traumatic brain tissue. Moreover, miR-873a-5p significantly inhibited LPS-induced microglial M1 phenotype transformation and the subsequent inflammation through decreased phosphorylation of ERK and NF-κB p65. This effect also greatly improved the modified neurological severity score (mNSS) and attenuated brain injury in a strictly controlled cortical impact mouse model.

CONCLUSIONS

Taken together, our research indicates that miRNAs in the exosomes derived from activated astrocytes play a key role in the astrocyte-microglia interaction. miR-873a-5p, as one of the main components of these astrocyte-derived exosomes, attenuated microglia-mediated neuroinflammation and improved neurological deficits following TBI by inhibiting the NF-κB signalling pathway. These findings suggest a potential role for miR-873a-5p in treating traumatic brain injury.

摘要

背景

星形胶质细胞和小胶质细胞之间的相互作用在创伤性脑损伤（TBI）导致的脑损伤和修复中起着至关重要的作用。最近的研究表明，外泌体作为一种有效的介质，参与细胞间的通讯。

方法

在本研究中，评估了 15 例创伤性脑损伤患者损伤区和水肿区的炎症因子和 miR-873a-5p 的表达。通过免疫荧光、Western blot 和电子显微镜检测星形胶质细胞分泌的外泌体。建立 TBI 小鼠模型和 LPS 诱导的原代小胶质细胞体外模型，研究 miR-873a-5p 过表达的外泌体在 TBI 诱导的神经损伤中的保护机制。

结果

我们发现，TBI 后，激活的星形胶质细胞来源的外泌体促进小胶质细胞 M2 表型转化。这些星形胶质细胞来源的外泌体中检测到超过 100 种 miRNA。miR-873a-5p 是一种在人类创伤性脑组织中高度表达的主要成分。此外，miR-873a-5p 通过降低 ERK 和 NF-κB p65 的磷酸化，显著抑制 LPS 诱导的小胶质细胞 M1 表型转化及随后的炎症反应。这种作用还极大地改善了改良神经严重程度评分（mNSS），并减轻了严格控制皮质撞击小鼠模型中的脑损伤。

结论

综上所述，我们的研究表明，激活的星形胶质细胞来源的外泌体中的 miRNA 在星形胶质细胞-小胶质细胞相互作用中起关键作用。miR-873a-5p 作为这些星形胶质细胞来源的外泌体的主要成分之一，通过抑制 NF-κB 信号通路，减轻小胶质细胞介导的神经炎症反应，改善 TBI 后的神经功能缺损。这些发现表明 miR-873a-5p 在治疗创伤性脑损伤方面具有潜在的作用。