TBX21 knockdown attenuates neuroinflammation induced by intracerebral hemorrhage via the SIRT1-WDR5-H3K4me3 axis

IF 3.7 3区医学 Q2 NEUROSCIENCES

Brain Research Bulletin Pub Date : 2025-06-02 DOI:10.1016/j.brainresbull.2025.111415

Zhichao Zou , Zhi Liu , Zhanwei Zhang , Xiaojing Li

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Abstract

Neuroinflammation is a key contributor to the development of secondary brain injury (SBI) following intracerebral hemorrhage (ICH). This study aimed to elucidate the role and underlying mechanisms of T-box transcription factor 21 (TBX21), a known regulator of type I inflammatory responses, in ICH-induced neuroinflammation. An in vitro oxygen-glucose deprivation (OGD) model using BV2 microglia and an in vivo autologous blood injection-induced ICH rat model were used to modulate TBX21 and sirtuin 1 (SIRT1) expression. The results showed that TBX21 knockdown significantly suppressed the OGD-induced release of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), decreased levels of the oxidative stress marker malondialdehyde (MDA), and restored the activities of antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). In addition, TBX21 knockdown reversed the OGD-induced upregulation of TBX21, WDR5, H3K4me3, cyclooxygenase-2 (COX2), and inducible nitric oxide synthase (iNOS), while enhancing SIRT1 expression. Mechanistically, TBX21 could directly bind to the promoter region of SIRT1 and suppress its transcription, and the protective effects of TBX21 knockdown were abolished by SIRT1 knockdown. In the ICH rat model, TBX21 knockdown or SIRT1 overexpression led to improvements in neurological severity scores, reductions in hematoma volume, and restoration of tight junction protein expression (occludin, claudin-3, and ZO-1). Collectively, these findings indicate that TBX21 promotes post-ICH neuroinflammation by repressing SIRT1, thereby enhancing WDR5-mediated H3K4me3 epigenetic modifications. TBX21 may therefore serve as a promising therapeutic target for mitigating SBI after ICH.

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TBX21敲低可通过SIRT1-WDR5-H3K4me3轴减弱脑出血引起的神经炎症。

神经炎症是脑出血（ICH）后继发性脑损伤（SBI）发展的关键因素。本研究旨在阐明T-box转录因子21 （TBX21）在ich诱导的神经炎症中的作用和潜在机制，TBX21是一种已知的I型炎症反应调节因子。采用体外BV2小胶质细胞氧糖剥夺（OGD）模型和体内自体血液注射诱导的脑出血大鼠模型调节TBX21和sirtuin 1 （SIRT1）的表达。结果表明，TBX21基因敲低可显著抑制ogd诱导的促炎细胞因子（IL-1β、IL-6、TNF-α）的释放，降低氧化应激标志物丙二醛（MDA）水平，恢复抗氧化酶超氧化物歧化酶（SOD）和谷胱甘肽过氧化物酶（GSH-Px）活性。此外，TBX21的敲低逆转了ogd诱导的TBX21、WDR5、H3K4me3、环氧化酶-2 （COX2）和诱导型一氧化氮合酶（iNOS）的上调，同时增强了SIRT1的表达。机制上，TBX21可直接结合SIRT1的启动子区抑制其转录，TBX21敲低的保护作用被SIRT1敲低所消除。在脑出血大鼠模型中，TBX21敲低或SIRT1过表达导致神经系统严重程度评分改善，血肿体积减少，紧密连接蛋白（occludin， claudin-3和ZO-1）表达恢复。总之，这些发现表明TBX21通过抑制SIRT1促进脑炎后神经炎症，从而增强wdr5介导的H3K4me3表观遗传修饰。因此，TBX21可能作为缓解脑出血后SBI的有希望的治疗靶点。

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

Brain Research Bulletin 医学-神经科学

CiteScore

6.90

自引率

2.60%

发文量

253

审稿时长

67 days

期刊介绍： The Brain Research Bulletin (BRB) aims to publish novel work that advances our knowledge of molecular and cellular mechanisms that underlie neural network properties associated with behavior, cognition and other brain functions during neurodevelopment and in the adult. Although clinical research is out of the Journal''s scope, the BRB also aims to publish translation research that provides insight into biological mechanisms and processes associated with neurodegeneration mechanisms, neurological diseases and neuropsychiatric disorders. The Journal is especially interested in research using novel methodologies, such as optogenetics, multielectrode array recordings and life imaging in wild-type and genetically-modified animal models, with the goal to advance our understanding of how neurons, glia and networks function in vivo.