Microglial SLC25A28 Deficiency Ameliorates the Brain Injury After Intracerebral Hemorrhage in Mice by Restricting Aerobic Glycolysis.
Microglial SLC25A28 Deficiency Ameliorates the Brain Injury After Intracerebral Hemorrhage in Mice by Restricting Aerobic Glycolysis.
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DOI：
10.1007/s10753-023-01931-1
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发表时间：
2023-12
期刊：
影响因子：
5.1
通讯作者：
Ruili Han;Lei Liu;Yuying Wang;Ruolin Wu;Ying Yang;Yuanlin Zhao;Lele Jian;Yuan Yuan-Yuan;Lijun Zhang;Yu Gu;Changjun Gao;Jing Ye
中科院分区：
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作者：
Ruili Han;Lei Liu;Yuying Wang;Ruolin Wu;Ying Yang;Yuanlin Zhao;Lele Jian;Yuan Yuan-Yuan;Lijun Zhang;Yu Gu;Changjun Gao;Jing Ye
小胶质细胞过度激活引起的神经炎症反应是脑出血后脑损伤的重要原因。铁稳态对小胶质细胞的激活至关重要，但其机制和因果关系仍需进一步研究。本研究旨在探讨线粒体铁转运蛋白SLC25A28在脑出血后小胶质细胞活化中的作用及其机制。采用纹状体内注射自体血建立脑出血模型，观察野生型和小胶质细胞特异性SLC25A28基因敲除小鼠脑出血后神经炎症、铁代谢和脑损伤的变化。在SLC25A28过表达或缺失的小胶质细胞中测定线粒体铁水平和小胶质细胞功能。细胞外酸化率（ECAR），乳酸生产，和糖酵解酶水平被用来确定有氧糖酵解。结果表明，脑出血可引起线粒体铁超载，并同步上调SLC 25 A28的表达，在体外，SLC 25 A28的过表达可增加小胶质细胞线粒体铁水平。有趣的是，小胶质细胞SLC25A28缺陷改善了ICH后小鼠的神经炎症、脑水肿、血脑屏障损伤和行为学改变。在机械上，SLC25A28缺陷通过限制有氧糖酵解来抑制小胶质细胞活化。锌原卟啉可降低SLC25A28的表达，减轻脑损伤。SLC25A28在脑出血后线粒体铁稳态和小胶质细胞活化中起重要作用，有望成为脑出血治疗的新靶点。
The microglia overactivation-induced neuroinflammation is a significant cause of the brain injury after intracerebral hemorrhage (ICH). Iron homeostasis is crucial for microglia activation, but the mechanism and causality still need further study. This study aimed to explore the roles and mechanism of the mitochondrial iron transporter SLC25A28 in microglia activation after ICH. Intrastriatal injection of autologous blood was used to establish ICH model, and the neuroinflammation, iron metabolism and brain injuries were assessed in wildtype or microglia-specific SLC25A28 knockout mice after ICH. Mitochondria iron levels and microglial function were determined in SLC25A28 overexpressed or deleted microglia. The extracellular acidification rate (ECAR), lactate production, and glycolytic enzyme levels were used to determine aerobic glycolysis. The results showed that ICH stimulated mitochondrial iron overload, and synchronously upregulated the SLC25A28 expression.In vitro, SLC25A28 overexpression increased mitochondrial iron levels in microglia. Interestingly, microglial SLC25A28 deficiency ameliorated neuroinflammation, brain edema, blood–brain barrier injury and ethological alterations in mice after ICH. Mechanically, SLC25A28 deficiency inhibited microglial activation by restricting the aerobic glycolysis. Moreover, zinc protoporphyrin could reduce SLC25A28 expression and mitigated brain injury. SLC25A28 plays crucial roles in mitochondrial iron homeostasis and microglia activation after ICH, and it might be a potential therapeutic target for ICH.