出血性脑卒中诱导的炎症反应性星形胶质细胞亚型破坏血脑屏障。
Hemorrhagic stroke-induced subtype of inflammatory reactive astrocytes disrupts blood-brain barrier.
机构信息
Shanghai Jiao Tong University Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
出版信息
J Cereb Blood Flow Metab. 2024 Jul;44(7):1102-1116. doi: 10.1177/0271678X241235008. Epub 2024 Feb 22.
Astrocytes undergo disease-specific transcriptomic changes upon brain injury. However, phenotypic changes of astrocytes and their functions remain unclear after hemorrhagic stroke. Here we reported hemorrhagic stroke induced a group of inflammatory reactive astrocytes with high expression of and , as well as inflammation-related genes , (C3), and . In addition, we demonstrated that depletion of microglia but not macrophages inhibited the expression of inflammation-related genes in inflammatory reactive astrocytes. RNA sequencing showed that blood-brain barrier (BBB) disruption-related gene matrix metalloproteinase-3 (MMP3) was highly upregulated in inflammatory reactive astrocytes. Pharmacological inhibition of MMP3 in astrocytes or specific deletion of astrocytic MMP3 reduced BBB disruption and improved neurological outcomes of hemorrhagic stroke mice. Our study demonstrated that hemorrhagic stroke induced a group of inflammatory reactive astrocytes that were actively involved in disrupting BBB through MMP3, highlighting a specific group of inflammatory reactive astrocytes as a critical driver for BBB disruption in neurological diseases.
脑损伤后星形胶质细胞发生特定的转录组变化。然而，脑出血后星形胶质细胞的表型变化及其功能仍不清楚。在这里，我们报道了脑出血诱导了一群具有高表达 和 的炎症反应性星形胶质细胞，以及炎症相关基因 、 （C3）和 。此外，我们还证明了小胶质细胞的耗竭而不是巨噬细胞的耗竭抑制了炎症反应性星形胶质细胞中炎症相关基因的表达。RNA 测序显示，血脑屏障（BBB）破坏相关基因基质金属蛋白酶-3（MMP3）在炎症反应性星形胶质细胞中高度上调。星形胶质细胞中 MMP3 的药理学抑制或星形胶质细胞特异性 MMP3 的缺失减少了 BBB 破坏，并改善了脑出血小鼠的神经预后。我们的研究表明，脑出血诱导了一群炎症反应性星形胶质细胞，它们通过 MMP3 积极参与破坏 BBB，突出了一类特定的炎症反应性星形胶质细胞作为神经疾病中 BBB 破坏的关键驱动因素。
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