Zhichao Zou , Zhi Liu , Zhanwei Zhang , Xiaojing Li
{"title":"TBX21敲低可通过SIRT1-WDR5-H3K4me3轴减弱脑出血引起的神经炎症。","authors":"Zhichao Zou , Zhi Liu , Zhanwei Zhang , Xiaojing Li","doi":"10.1016/j.brainresbull.2025.111415","DOIUrl":null,"url":null,"abstract":"<div><div>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 <em>in vitro</em> oxygen-glucose deprivation (OGD) model using BV2 microglia and an <em>in vivo</em> 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.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"229 ","pages":"Article 111415"},"PeriodicalIF":3.7000,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"TBX21 knockdown attenuates neuroinflammation induced by intracerebral hemorrhage via the SIRT1-WDR5-H3K4me3 axis\",\"authors\":\"Zhichao Zou , Zhi Liu , Zhanwei Zhang , Xiaojing Li\",\"doi\":\"10.1016/j.brainresbull.2025.111415\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>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 <em>in vitro</em> oxygen-glucose deprivation (OGD) model using BV2 microglia and an <em>in vivo</em> 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.</div></div>\",\"PeriodicalId\":9302,\"journal\":{\"name\":\"Brain Research Bulletin\",\"volume\":\"229 \",\"pages\":\"Article 111415\"},\"PeriodicalIF\":3.7000,\"publicationDate\":\"2025-06-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Brain Research Bulletin\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0361923025002278\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Brain Research Bulletin","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0361923025002278","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
TBX21 knockdown attenuates neuroinflammation induced by intracerebral hemorrhage via the SIRT1-WDR5-H3K4me3 axis
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.
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.