KLF7阻断MKNK2/HIF-1通路介导的M1小胶质细胞极化以改善缺血性卒中诱导的神经损伤

IF 2.7 3区心理学 Q2 BEHAVIORAL SCIENCES

Brain and Behavior Pub Date : 2025-09-09 DOI:10.1002/brb3.70850

Ran Wei, Shuang Li, Lei Tang

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引用次数: 0

摘要

背景缺血性脑卒中是一种常见的神经系统疾病，经济负担沉重，但缺乏有效的药物。本研究旨在探索MAP激酶相互作用丝氨酸/苏氨酸蛋白激酶2 （MKNK2）的机制，MKNK2是一种富含缺氧诱导因子-1 （HIF-1）信号的基因，在is相关的神经损伤中起作用。方法采用大脑中动脉闭塞/再灌注（MCAO/R）模型和氧葡萄糖剥夺/再氧合（OGD/R）模型。用靶基因敲低或过表达的慢病毒载体感染大鼠，然后用MCAO/R进行2,3,5-三苯四氮氯化铵、HE、Fluoro-Jade C和TUNEL、酶联免疫吸附试验、免疫组织化学和神经功能缺损评估。采用ChIP和双荧光素酶法分析kruepel -like factor 7 （KLF7）对MKNK2的调控作用。通过转染敲低或过表达质粒，证实了KLF7/MKNK2/HIF-1轴对大鼠小胶质细胞M1或M2极化的影响。结果MCAO/ r处理的大鼠脑组织和OGD/ r处理的大鼠小胶质细胞显示MKNK2上调，HIF-1信号通路激活，KLF7表达下调。MKNK2的下调抑制HIF-1信号通路和M1小胶质细胞极化，而促进M2极化。KLF7抑制MKNK2转录，从而在体外达到与MKNK2敲低相同的效果，通过联合过表达MKNK2来逆转。敲低MKNK2或过表达KLF7可改善MCAO/ r诱导的大鼠脑损伤和神经损伤。MKNK2过表达逆转了KLF7过表达对大鼠病理性脑损伤的缓解作用。结论IS后KLF7表达的显著下调通过mknk2介导的HIF-1通路加重病理性脑损伤。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

KLF7 Blocks MKNK2/HIF-1 Pathway-Mediated M1 Microglia Polarization to Ameliorate Ischemic Stroke-Induced Neurological Injury

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KLF7 Blocks MKNK2/HIF-1 Pathway-Mediated M1 Microglia Polarization to Ameliorate Ischemic Stroke-Induced Neurological Injury

Background

Ischemic stroke (IS) is a common neurological disease with a significant financial burden but lacks effective drugs. This study sought to explore the mechanisms underlying MAP kinase-interacting serine/threonine-protein kinase 2 (MKNK2), a gene enriched in the hypoxia-inducible factor-1 (HIF-1) signaling, in IS-related neurological injury.

Methods

Middle cerebral artery occlusion/reperfusion (MCAO/R) and oxygen-glucose deprivation/reoxygenation (OGD/R) models were used in vivo and in vitro. Rats were infected with lentiviral vectors harboring knockdown or overexpression of the target genes, followed by MCAO/R to conduct 2,3,5-triphenyltetrazolium chloride, HE, Fluoro-Jade C, and TUNEL, enzyme-linked immunosorbent assay, immunohistochemistry, and neurological deficits assessment. The regulation of Krueppel-like factor 7 (KLF7) on MKNK2 was analyzed by ChIP and dual-luciferase assays. The effects of the KLF7/MKNK2/HIF-1 axis on the M1 or M2 polarization of rat microglia were demonstrated by the transfection of knockdown or overexpression plasmids into the cells.

Results

MCAO/R-treated rat brain tissues and OGD/R-treated rat microglia showed MKNK2 upregulation along with activation of the HIF-1 signaling, whereas KLF7 expression was downregulated. Knockdown of MKNK2 inhibited the HIF-1 signaling and M1 microglia polarization, whereas it promoted M2 polarization. KLF7 repressed the MKNK2 transcription, thereby achieving the same effect as the knockdown of MKNK2 in vitro, which was reversed by combined overexpression of MKNK2. Knockdown of MKNK2 or overexpression of KLF7 ameliorated MCAO/R-induced brain damage and neurological injury in rats. MKNK2 overexpression reversed the alleviating effect of KLF7 overexpression on pathological brain injury in rats.

Conclusion

Significant downregulation of KLF7 expression after IS exacerbated pathological brain damage through the MKNK2-mediated HIF-1 pathway.

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来源期刊

Brain and Behavior BEHAVIORAL SCIENCES-NEUROSCIENCES

CiteScore

5.30

自引率

0.00%

发文量

352

审稿时长

14 weeks

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