小胶质细胞
促炎细胞因子
神经炎症
HDAC3型
神经科学
条件基因敲除
细胞生物学
生物
医学
免疫学
癌症研究
炎症
生物化学
基因
组蛋白
组蛋白脱乙酰基酶
表型
作者
Yue Zhang,Jiaying Li,Yongfang Zhao,Yichen Huang,Ziyu Shi,Hailian Wang,Hui Cao,Chenran Wang,Yana Wang,Di Chen,Shuning Chen,Shan Meng,Yangfan Wang,Yueyan Zhu,Yan Jiang,Ye Gong,Yanqin Gao
出处
期刊:Science Advances
[American Association for the Advancement of Science (AAAS)]
日期:2024-03-06
卷期号:10 (10)
被引量:5
标识
DOI:10.1126/sciadv.ade6900
摘要
The accumulation of self-renewed polarized microglia in the penumbra is a critical neuroinflammatory process after ischemic stroke, leading to secondary demyelination and neuronal loss. Although known to regulate tumor cell proliferation and neuroinflammation, HDAC3’s role in microgliosis and microglial polarization remains unclear. We demonstrated that microglial HDAC3 knockout (HDAC3-miKO) ameliorated poststroke long-term functional and histological outcomes. RNA-seq analysis revealed mitosis as the primary process affected in HDAC3-deficent microglia following stroke. Notably, HDAC3-miKO specifically inhibited proliferation of proinflammatory microglia without affecting anti-inflammatory microglia, preventing microglial transition to a proinflammatory state. Moreover, ATAC-seq showed that HDAC3-miKO induced closing of accessible regions enriched with PU.1 motifs. Overexpressing microglial PU.1 via an AAV approach reversed HDAC3-miKO–induced proliferation inhibition and protective effects on ischemic stroke, indicating PU.1 as a downstream molecule that mediates HDAC3’s effects on stroke. These findings uncovered that HDAC3/PU.1 axis, which mediated differential proliferation-related reprogramming in different microglia populations, drove poststroke inflammatory state transition, and contributed to pathophysiology of ischemic stroke.
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