Exosomal Src from hypoxic vascular smooth muscle cells exacerbates ischemic brain injury by promoting M1 microglial polarization

IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Neurochemistry international Pub Date : 2024-07-29 DOI:10.1016/j.neuint.2024.105819
Xiaoting Zhang , Jingpei Guo , Junbin Liu , Junfeng Liu , Zhaozhu Li , Jiayao Chen , Jiawei Jiang , Ke Zhang , Bin Zhou
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Abstract

Inflammatory response mediated by M1 microglia is a crucial factor leading to the exacerbation of brain injury after ischemic stroke (IS). Under the stimulation of IS, vascular smooth muscle cells (VSMCs) switch to the synthetic phenotype characterized by exosome secretion. Previous studies have shown that exosomes play an important role in the regulation of microglial polarization. We reported that exosomes derived from primary human brain VSMCs under hypoxia (HExos), but not those under normoxia (Exos), significantly promoted primary human microglia (HM1900) shift to M1 phenotype. Proteomic analysis showed that the Src protein enriched in HExos was a potential pro-inflammatory mediator. In vitro experiments showed that the expression of Src and M1 markers were upregulated in HM1900 co-incubated with HExos. However, the Src inhibitor dasatinib (DAS) significantly promoted the transformation of HM1900 phenotype from M1 to M2. In vivo experiments of pMCAO mice also revealed that DAS could effectively inhibit the activation of M1 microglia/macrophages, protect neurons from apoptosis, and improve neuronal function. These data suggested that hypoxic-VSMCs-derived exosomes were involved in post-IS inflammation by promoting M1 microglial polarization through Src transmission. Targeting inhibition of Src potentially acts as an effective strategy for treating brain injury after IS.

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缺氧血管平滑肌细胞外泌体 Src 通过促进 M1 小胶质细胞极化加剧缺血性脑损伤
由 M1 小胶质细胞介导的炎症反应是导致缺血性中风(IS)后脑损伤加重的关键因素。在缺血性脑卒中的刺激下,血管平滑肌细胞(VSMC)转为以分泌外泌体为特征的合成表型。以前的研究表明,外泌体在调节小胶质细胞极化方面发挥着重要作用。我们报告说,在缺氧(HExos)条件下,从原代人脑 VSMCs 提取的外泌体可显著促进原代人小胶质细胞(HM1900)向 M1 表型转变,而在正常缺氧(Exos)条件下则不然。蛋白质组分析表明,HExos 中富集的 Src 蛋白是一种潜在的促炎介质。体外实验表明,HM1900 与 HExos 共同孵育时,Src 和 M1 标志物的表达上调。然而,Src抑制剂达沙替尼(DAS)能显著促进HM1900表型从M1向M2转变。pMCAO小鼠的体内实验也显示,DAS能有效抑制M1小胶质细胞/巨噬细胞的活化,保护神经元免于凋亡,并改善神经元功能。这些数据表明,缺氧-VSMCs衍生的外泌体通过Src传递促进M1小胶质细胞极化,从而参与了IS后炎症。靶向抑制Src可能是治疗IS后脑损伤的有效策略。
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来源期刊
Neurochemistry international
Neurochemistry international 医学-神经科学
CiteScore
8.40
自引率
2.40%
发文量
128
审稿时长
37 days
期刊介绍: Neurochemistry International is devoted to the rapid publication of outstanding original articles and timely reviews in neurochemistry. Manuscripts on a broad range of topics will be considered, including molecular and cellular neurochemistry, neuropharmacology and genetic aspects of CNS function, neuroimmunology, metabolism as well as the neurochemistry of neurological and psychiatric disorders of the CNS.
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