整合转录组分析发现 Cd72 是实验性缺血性中风后小胶质细胞中的新型促炎因子。

IF 4.6 2区 医学 Q1 NEUROSCIENCES Experimental Neurology Pub Date : 2024-09-24 DOI:10.1016/j.expneurol.2024.114974
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引用次数: 0

摘要

缺血性中风仍然是导致全球死亡和残疾的主要原因,而神经炎症在决定患者预后方面起着至关重要的作用。小胶质细胞是大脑的常驻免疫细胞,既能通过释放神经毒性介质和过度吞噬作用加剧神经炎症和神经元损伤,也能通过产生抗炎细胞因子和清除碎片帮助恢复。然而,缺血性中风后小胶质细胞活化和极化的分子机制尚未得到很好的阐明。在这项研究中,我们在大脑中动脉闭塞/再灌注(MCAO/R)的小鼠模型中结合了综合转录组分析和实验验证,以探索小胶质细胞的异质性并确定缺血性中风的关键调控因子。生物信息学分析发现,Cd72 是缺血相关小胶质细胞表型中的一种新型促炎调节因子。我们观察到 MCAO/R 后小胶质细胞中 Cd72 的明显上调,使用 CX3CR1Cre/ERT2 小鼠和 Cre 重组酶依赖性腺相关病毒选择性敲除 Cd72 可减少 MCAO/R 诱导的梗死体积、神经元凋亡和神经功能缺损。此外,Cd72在小胶质细胞中的表达与促炎途径和细胞因子(包括TNF-α、IL-1β和IL-6)呈正相关。敲除 Cd72 能明显降低这些促炎因子,突出了其作为减轻缺血性中风炎症的治疗靶点的潜力。总之,本研究发现 Cd72 是缺血性中风后小胶质细胞中的一个关键促炎调节因子,敲除 Cd72 能有效减轻神经炎症和相关脑损伤,从而凸显了 Cd72 作为治疗靶点的潜力。
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Integrative transcriptomic analysis reveals Cd72 as a novel pro-inflammatory factor in microglia following experimental ischemic stroke
Ischemic stroke remains a leading cause of global mortality and disability, with neuroinflammation playing a critical role in determining patient outcomes. Microglia, the brain's resident immune cells, can both exacerbate neuroinflammation and neuronal damage by releasing neurotoxic mediators and engaging in excessive phagocytosis, while also aiding recovery through the production of anti-inflammatory cytokines and debris clearance. However, the molecular mechanisms governing microglial activation and polarization after ischemic stroke are not well elucidated. In this study, we combined integrative transcriptomic analyses with experimental validation in a murine model of middle cerebral artery occlusion/reperfusion (MCAO/R) to explore microglial heterogeneity and identify key regulatory factors in ischemic stroke. Bioinformatics analysis identified Cd72 as a novel pro-inflammatory modulator within ischemia-associated microglial phenotypes. We observed significant upregulation of Cd72 in microglia following MCAO/R, and selective knockdown of Cd72 using CX3CR1Cre/ERT2 mice and Cre recombinase-dependent adeno-associated virus reduced MCAO/R-induced infarct volume, neuronal apoptosis, and neurological deficits. Furthermore, Cd72 expression in microglia was positively correlated with pro-inflammatory pathways and cytokines, including TNF-α, IL-1β, and IL-6. Knockdown of Cd72 significantly reduced these pro-inflammatory factors, highlighting its potential as a therapeutic target for mitigating inflammation in ischemic stroke. In conclusion, this study identifies Cd72 as a critical pro-inflammatory regulator in microglia following ischemic stroke, with its knockdown effectively reducing neuroinflammation and associated brain injury, highlighting Cd72 as a promising therapeutic target.
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来源期刊
Experimental Neurology
Experimental Neurology 医学-神经科学
CiteScore
10.10
自引率
3.80%
发文量
258
审稿时长
42 days
期刊介绍: Experimental Neurology, a Journal of Neuroscience Research, publishes original research in neuroscience with a particular emphasis on novel findings in neural development, regeneration, plasticity and transplantation. The journal has focused on research concerning basic mechanisms underlying neurological disorders.
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