Center of Interventional Medicine, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, 519000, China; Center of Cerebrovascular Disease, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, 519000, China; Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province, 519000, China.
Department of Medical Ultrasonics, The Fourth People's Hospital of Nanhai District of Foshan City, Foshan, Guangdong Province, 528211, China.
Neurochem Int. 2024 Oct;179:105819. doi: 10.1016/j.neuint.2024.105819. Epub 2024 Jul 29.
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.
M1 小胶质细胞介导的炎症反应是导致缺血性脑卒中（IS）后脑损伤加重的关键因素。在 IS 的刺激下，血管平滑肌细胞（VSMCs）转变为以分泌外体为特征的合成表型。先前的研究表明，外体在调节小胶质细胞极化中发挥重要作用。我们报道了缺氧条件下（HExos）源自原代人脑 VSMCs 的外体，但不是正常氧条件下（Exos）的外体，可显著促进原代人脑小胶质细胞（HM1900）向 M1 表型转变。蛋白质组学分析表明，HExos 中富含的Src 蛋白是一种潜在的促炎介质。体外实验表明，与 HExos 共孵育的 HM1900 中 Src 和 M1 标志物的表达上调。然而，Src 抑制剂达沙替尼（DAS）显著促进了 HM1900 表型从 M1 向 M2 的转变。pMCAO 小鼠的体内实验也表明，DAS 可有效抑制 M1 小胶质细胞/巨噬细胞的激活，保护神经元免于凋亡，并改善神经元功能。这些数据表明，缺氧条件下的 VSMCs 衍生的外体通过 Src 传递促进 M1 小胶质细胞极化，从而参与 IS 后的炎症反应。靶向抑制 Src 可能是治疗 IS 后脑损伤的有效策略。
