{"title":"Toll-Like受体介导树突状细胞对脑出血小鼠Treg/Th17平衡的对立效应","authors":"Li Zhu, Junkui Shang, Yinuo Li, Zhiying Zhang, Peiji Fu, Yan Zong, Shuai Chen, Junmin Wang, Jiewen Zhang, Jian Wang, Chao Jiang","doi":"10.1161/STROKEAHA.124.046394","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Dendritic cells (DCs) regulate the immune response associated with T lymphocytes, but their role in stroke remains unclear. In this study, we investigated the causal relationship between DCs and T-cell response in intracerebral hemorrhage (ICH) by focusing on TLRs (toll-like receptors) that may modulate the function of DCs.</p><p><strong>Methods: </strong>We studied the effects of TLR4, TLR2, and TLR9 on DC-mediated T-cell response and the outcomes of ICH using male C57BL/6 and CD11c-DTx (diphtheria toxin) receptor mice. We administered specific agents intraperitoneally or orally and evaluated the results using flow cytometry, real-time polymerase chain reaction, Western blotting, immunofluorescence staining, histopathology, and behavioral tests.</p><p><strong>Results: </strong>TLR4 and TLR2 activation induces DC maturation and reduces the ratio of regulatory T to T-helper 17 cells in the brain and periphery after ICH. When either of these receptors is activated, it can worsen neuroinflammation and exacerbate ICH outcomes. TLR9 also promotes DC maturation, stabilizing the number of DCs, particularly conventional DCs. TLR9 has the opposite effects on regulatory T/T-helper 17 balance, neuroinflammation, and ICH outcomes compared with TLR4 and TLR2. Upon stimulation, TLR4 and TLR9 may achieve these effects through the p38-MAPK (p38-mitogen-activated protein kinase)/MyD88 (myeloid differentiation primary response gene 88) and indoleamine 2,3-dioxygenase 1 (IDO1)/GCN2 (general control nonderepressible 2) signaling pathways, respectively. DCs act as intermediaries for TLR-mediated T-cell response.</p><p><strong>Conclusions: </strong>TLR-mediated opposing effects of DCs on T-cell response may provide novel strategies to treat ICH.</p>","PeriodicalId":21989,"journal":{"name":"Stroke","volume":null,"pages":null},"PeriodicalIF":7.8000,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Toll-Like Receptors Mediate Opposing Dendritic Cell Effects on Treg/Th17 Balance in Mice With Intracerebral Hemorrhage.\",\"authors\":\"Li Zhu, Junkui Shang, Yinuo Li, Zhiying Zhang, Peiji Fu, Yan Zong, Shuai Chen, Junmin Wang, Jiewen Zhang, Jian Wang, Chao Jiang\",\"doi\":\"10.1161/STROKEAHA.124.046394\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Dendritic cells (DCs) regulate the immune response associated with T lymphocytes, but their role in stroke remains unclear. In this study, we investigated the causal relationship between DCs and T-cell response in intracerebral hemorrhage (ICH) by focusing on TLRs (toll-like receptors) that may modulate the function of DCs.</p><p><strong>Methods: </strong>We studied the effects of TLR4, TLR2, and TLR9 on DC-mediated T-cell response and the outcomes of ICH using male C57BL/6 and CD11c-DTx (diphtheria toxin) receptor mice. We administered specific agents intraperitoneally or orally and evaluated the results using flow cytometry, real-time polymerase chain reaction, Western blotting, immunofluorescence staining, histopathology, and behavioral tests.</p><p><strong>Results: </strong>TLR4 and TLR2 activation induces DC maturation and reduces the ratio of regulatory T to T-helper 17 cells in the brain and periphery after ICH. When either of these receptors is activated, it can worsen neuroinflammation and exacerbate ICH outcomes. TLR9 also promotes DC maturation, stabilizing the number of DCs, particularly conventional DCs. TLR9 has the opposite effects on regulatory T/T-helper 17 balance, neuroinflammation, and ICH outcomes compared with TLR4 and TLR2. Upon stimulation, TLR4 and TLR9 may achieve these effects through the p38-MAPK (p38-mitogen-activated protein kinase)/MyD88 (myeloid differentiation primary response gene 88) and indoleamine 2,3-dioxygenase 1 (IDO1)/GCN2 (general control nonderepressible 2) signaling pathways, respectively. DCs act as intermediaries for TLR-mediated T-cell response.</p><p><strong>Conclusions: </strong>TLR-mediated opposing effects of DCs on T-cell response may provide novel strategies to treat ICH.</p>\",\"PeriodicalId\":21989,\"journal\":{\"name\":\"Stroke\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":7.8000,\"publicationDate\":\"2024-08-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Stroke\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1161/STROKEAHA.124.046394\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/6/26 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Stroke","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1161/STROKEAHA.124.046394","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/6/26 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
引用次数: 0
摘要
背景:树突状细胞(DC)调节与T淋巴细胞相关的免疫反应,但它们在中风中的作用仍不清楚。在本研究中,我们通过关注可能调节 DC 功能的 TLR(类收费受体),研究了 DC 与脑内出血(ICH)中 T 细胞反应之间的因果关系:我们使用雄性 C57BL/6 和 CD11c-DTx(白喉毒素)受体小鼠研究了 TLR4、TLR2 和 TLR9 对 DC 介导的 T 细胞反应和 ICH 后果的影响。我们腹腔注射或口服了特定的药物,并使用流式细胞术、实时聚合酶链反应、Western 印迹、免疫荧光染色、组织病理学和行为测试对结果进行了评估:结果:TLR4 和 TLR2 激活可诱导 DC 成熟,并降低 ICH 后大脑和外周调节性 T 细胞与 T 辅助 17 细胞的比例。当这两种受体中的任何一种被激活时,都会加重神经炎症并加剧 ICH 的后果。TLR9 还能促进 DC 成熟,稳定 DC(尤其是传统 DC)的数量。与 TLR4 和 TLR2 相比,TLR9 对调节性 T/T-helper 17 平衡、神经炎症和 ICH 结果的影响正好相反。受刺激后,TLR4 和 TLR9 可分别通过 p38-MAPK(p38-mitogen-activated protein kinase)/MyD88(myeloid differentiation primary response gene 88)和吲哚胺 2,3-二氧化酶 1(IDO1)/GCN2(general control nonderepressible 2)信号通路达到上述效果。DC是TLR介导的T细胞反应的中介:结论:TLR介导的DC对T细胞反应的相反作用可能为治疗ICH提供新的策略。
Toll-Like Receptors Mediate Opposing Dendritic Cell Effects on Treg/Th17 Balance in Mice With Intracerebral Hemorrhage.
Background: Dendritic cells (DCs) regulate the immune response associated with T lymphocytes, but their role in stroke remains unclear. In this study, we investigated the causal relationship between DCs and T-cell response in intracerebral hemorrhage (ICH) by focusing on TLRs (toll-like receptors) that may modulate the function of DCs.
Methods: We studied the effects of TLR4, TLR2, and TLR9 on DC-mediated T-cell response and the outcomes of ICH using male C57BL/6 and CD11c-DTx (diphtheria toxin) receptor mice. We administered specific agents intraperitoneally or orally and evaluated the results using flow cytometry, real-time polymerase chain reaction, Western blotting, immunofluorescence staining, histopathology, and behavioral tests.
Results: TLR4 and TLR2 activation induces DC maturation and reduces the ratio of regulatory T to T-helper 17 cells in the brain and periphery after ICH. When either of these receptors is activated, it can worsen neuroinflammation and exacerbate ICH outcomes. TLR9 also promotes DC maturation, stabilizing the number of DCs, particularly conventional DCs. TLR9 has the opposite effects on regulatory T/T-helper 17 balance, neuroinflammation, and ICH outcomes compared with TLR4 and TLR2. Upon stimulation, TLR4 and TLR9 may achieve these effects through the p38-MAPK (p38-mitogen-activated protein kinase)/MyD88 (myeloid differentiation primary response gene 88) and indoleamine 2,3-dioxygenase 1 (IDO1)/GCN2 (general control nonderepressible 2) signaling pathways, respectively. DCs act as intermediaries for TLR-mediated T-cell response.
Conclusions: TLR-mediated opposing effects of DCs on T-cell response may provide novel strategies to treat ICH.
期刊介绍:
Stroke is a monthly publication that collates reports of clinical and basic investigation of any aspect of the cerebral circulation and its diseases. The publication covers a wide range of disciplines including anesthesiology, critical care medicine, epidemiology, internal medicine, neurology, neuro-ophthalmology, neuropathology, neuropsychology, neurosurgery, nuclear medicine, nursing, radiology, rehabilitation, speech pathology, vascular physiology, and vascular surgery.
The audience of Stroke includes neurologists, basic scientists, cardiologists, vascular surgeons, internists, interventionalists, neurosurgeons, nurses, and physiatrists.
Stroke is indexed in Biological Abstracts, BIOSIS, CAB Abstracts, Chemical Abstracts, CINAHL, Current Contents, Embase, MEDLINE, and Science Citation Index Expanded.