The opposite effect of ELP4 and ZEB2 on TCF7L2-mediated microglia polarization in ischemic stroke.

IF 3.6 3区生物学 Q3 CELL BIOLOGY Journal of Cell Communication and Signaling Pub Date : 2025-01-16 eCollection Date: 2025-03-01 DOI:10.1002/ccs3.12061

Xiao-Li Min, Sixian Lin, Jia-Yi Hu, Rui Jing, Qing Zhao, Fei-Fei Shang, Yong Zeng

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Abstract

Microglia M1 polarization plays important role in the development of ischemic stroke (IS). This study explored the role of transcription factor 7 like 2 (TCF7L2) in regulating microglia M1 polarization during IS. TTC staining was used to determine the cerebral infarction, and Nissl staining was applied to examine neuronal injury. The secretion levels of cytokines were measured using ELISA. The interaction between Zinc finger E-Box binding homeobox 2 (ZEB2) and TCF7L2 was analyzed by Co-IP, and H3K27ac enrichment in the TCF7L2 promoter was detected by ChIP assay. TCF7L2 knockdown reduced MCAO/R-induced mice cerebral injury. TCF7L2 silencing or TAK-242 (TLR4 antagonist) injection inhibited OGD/R-induced microglia M1 polarization by repressing the TLR4/NF-κB signal, and TCF7L2 knockdown combined with TAK-242 treatment further inhibited microglia M1 polarization. TCF7L2 promoted transcriptional activation of TLR4. ELP4 enhanced H3K27ac-mediated transcriptional activation of TCF7L2, and ZEB2 promoted the K48-linked ubiquitination of TCF7L2. TCF7L2 overexpression abolished the inhibitory effect of ELP4 knockdown or ZEB2 overexpression on OGD/R-induced microglia M1 polarization. TCF7L2 exacerbated cerebral injury by promoting microglia M1 polarization during IS progression. Mechanistically, ELP4 promoted TCF7L2 expression by promoting H3K27ac enrichment in the TCF7L2 promoter, while ZEB2 promoted TCF7L2 ubiquitination degradation.

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ELP4和ZEB2对缺血性脑卒中tcf7l2介导的小胶质细胞极化的相反作用。

小胶质细胞M1极化在缺血性脑卒中（IS）的发生发展中起重要作用。本研究探讨了转录因子7 like 2 （TCF7L2）在IS期间调节小胶质细胞M1极化的作用。TTC染色检测脑梗死，Nissl染色检测神经元损伤。ELISA法检测细胞因子分泌水平。采用Co-IP分析锌指E-Box结合同源盒2 （ZEB2）与TCF7L2的相互作用，采用ChIP检测TCF7L2启动子中H3K27ac的富集情况。TCF7L2敲除可减少MCAO/ r诱导的小鼠脑损伤。TCF7L2沉默或TAK-242 （TLR4拮抗剂）注射通过抑制TLR4/NF-κB信号抑制OGD/ r诱导的小胶质细胞M1极化，TCF7L2敲除联合TAK-242治疗进一步抑制小胶质细胞M1极化。TCF7L2促进TLR4的转录激活。ELP4增强了h3k27ac介导的TCF7L2的转录激活，ZEB2促进了k48相关的TCF7L2泛素化。TCF7L2过表达可消除ELP4敲低或ZEB2过表达对OGD/ r诱导的小胶质细胞M1极化的抑制作用。在IS进展过程中，TCF7L2通过促进小胶质细胞M1极化加重脑损伤。机制上，ELP4通过促进TCF7L2启动子中H3K27ac的富集促进TCF7L2表达，而ZEB2促进TCF7L2泛素化降解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Cell Communication and Signaling CELL BIOLOGY-

CiteScore

6.40

自引率

4.90%

发文量

期刊介绍： The Journal of Cell Communication and Signaling provides a forum for fundamental and translational research. In particular, it publishes papers discussing intercellular and intracellular signaling pathways that are particularly important to understand how cells interact with each other and with the surrounding environment, and how cellular behavior contributes to pathological states. JCCS encourages the submission of research manuscripts, timely reviews and short commentaries discussing recent publications, key developments and controversies. Research manuscripts can be published under two different sections : In the Pathology and Translational Research Section (Section Editor Andrew Leask) , manuscripts report original research dealing with celllular aspects of normal and pathological signaling and communication, with a particular interest in translational research. In the Molecular Signaling Section (Section Editor Satoshi Kubota) manuscripts report original signaling research performed at molecular levels with a particular interest in the functions of intracellular and membrane components involved in cell signaling.