Dual role of TLR4 in bacterial meningitis through regulating endothelial pyroptosis and inflammatory response during extraintestinal pathogenic Escherichia coli infection
Bacterial meningitis is a severe central nervous system infection with incompletely understood pathogenesis. Here, we investigated the role of Toll-like receptor 4 (TLR4) in blood-brain barrier disruption induced by extraintestinal pathogenic Escherichia coli (ExPEC). In vitro studies revealed that...
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Frontiers Media S.A.
2025-08-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1581696/full |
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| author | Kaixiang Jia Yangyang Du Weixian Lin Xuefeng Cao Xuefeng Cao Jialu Zhang Jialu Zhang Lianci Peng Lianci Peng Zhiwei Li Zhiwei Li Rendong Fang Rendong Fang |
| author_facet | Kaixiang Jia Yangyang Du Weixian Lin Xuefeng Cao Xuefeng Cao Jialu Zhang Jialu Zhang Lianci Peng Lianci Peng Zhiwei Li Zhiwei Li Rendong Fang Rendong Fang |
| author_sort | Kaixiang Jia |
| collection | DOAJ |
| description | Bacterial meningitis is a severe central nervous system infection with incompletely understood pathogenesis. Here, we investigated the role of Toll-like receptor 4 (TLR4) in blood-brain barrier disruption induced by extraintestinal pathogenic Escherichia coli (ExPEC). In vitro studies revealed that ExPEC infection upregulated TLR4 expression in human brain microvascular endothelial cells and induced pyroptosis and tight junction protein degradation. TLR4 inhibition by TAK-242 significantly reduced pyroptosis and inflammatory responses but exacerbated tight junction disruption and bacterial invasion. In macrophages, TLR4 inhibition similarly attenuated pyroptosis and inflammatory responses. Interestingly, despite enhanced blood-brain barrier disruption and increased bacterial burden, TLR4-deficient mice showed significantly improved survival. Transcriptome analysis revealed that TLR4 deficiency triggered comprehensive reprogramming of host responses, characterized by both suppressed inflammatory damage and enhanced tissue homeostatic processes. This study demonstrates for the first time that endothelial pyroptosis is a novel mechanism for ExPEC-induced blood-brain barrier disruption and reveals the crucial role of TLR4 in balancing protective and destructive host responses, providing new insights for therapeutic strategies against bacterial meningitis. |
| format | Article |
| id | doaj-art-ff14beb164354437b7ed46cd4824ac23 |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-ff14beb164354437b7ed46cd4824ac232025-08-20T03:32:08ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-08-011610.3389/fimmu.2025.15816961581696Dual role of TLR4 in bacterial meningitis through regulating endothelial pyroptosis and inflammatory response during extraintestinal pathogenic Escherichia coli infectionKaixiang Jia0Yangyang Du1Weixian Lin2Xuefeng Cao3Xuefeng Cao4Jialu Zhang5Jialu Zhang6Lianci Peng7Lianci Peng8Zhiwei Li9Zhiwei Li10Rendong Fang11Rendong Fang12Joint International Research Laboratory of Animal Health and Animal Food Safety, College of Veterinary Medicine, Southwest University, Chongqing, ChinaJoint International Research Laboratory of Animal Health and Animal Food Safety, College of Veterinary Medicine, Southwest University, Chongqing, ChinaDepartment of Microbiology and Immunology, Stanford University, Stanford, CA, United StatesJoint International Research Laboratory of Animal Health and Animal Food Safety, College of Veterinary Medicine, Southwest University, Chongqing, ChinaNational Center of Technology Innovation for Pigs, Chongqing, ChinaJoint International Research Laboratory of Animal Health and Animal Food Safety, College of Veterinary Medicine, Southwest University, Chongqing, ChinaNational Center of Technology Innovation for Pigs, Chongqing, ChinaJoint International Research Laboratory of Animal Health and Animal Food Safety, College of Veterinary Medicine, Southwest University, Chongqing, ChinaNational Center of Technology Innovation for Pigs, Chongqing, ChinaJoint International Research Laboratory of Animal Health and Animal Food Safety, College of Veterinary Medicine, Southwest University, Chongqing, ChinaNational Center of Technology Innovation for Pigs, Chongqing, ChinaJoint International Research Laboratory of Animal Health and Animal Food Safety, College of Veterinary Medicine, Southwest University, Chongqing, ChinaNational Center of Technology Innovation for Pigs, Chongqing, ChinaBacterial meningitis is a severe central nervous system infection with incompletely understood pathogenesis. Here, we investigated the role of Toll-like receptor 4 (TLR4) in blood-brain barrier disruption induced by extraintestinal pathogenic Escherichia coli (ExPEC). In vitro studies revealed that ExPEC infection upregulated TLR4 expression in human brain microvascular endothelial cells and induced pyroptosis and tight junction protein degradation. TLR4 inhibition by TAK-242 significantly reduced pyroptosis and inflammatory responses but exacerbated tight junction disruption and bacterial invasion. In macrophages, TLR4 inhibition similarly attenuated pyroptosis and inflammatory responses. Interestingly, despite enhanced blood-brain barrier disruption and increased bacterial burden, TLR4-deficient mice showed significantly improved survival. Transcriptome analysis revealed that TLR4 deficiency triggered comprehensive reprogramming of host responses, characterized by both suppressed inflammatory damage and enhanced tissue homeostatic processes. This study demonstrates for the first time that endothelial pyroptosis is a novel mechanism for ExPEC-induced blood-brain barrier disruption and reveals the crucial role of TLR4 in balancing protective and destructive host responses, providing new insights for therapeutic strategies against bacterial meningitis.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1581696/fullbacterial meningitistoll-like receptor 4blood-brain barrierendothelial pyroptosishost response |
| spellingShingle | Kaixiang Jia Yangyang Du Weixian Lin Xuefeng Cao Xuefeng Cao Jialu Zhang Jialu Zhang Lianci Peng Lianci Peng Zhiwei Li Zhiwei Li Rendong Fang Rendong Fang Dual role of TLR4 in bacterial meningitis through regulating endothelial pyroptosis and inflammatory response during extraintestinal pathogenic Escherichia coli infection Frontiers in Immunology bacterial meningitis toll-like receptor 4 blood-brain barrier endothelial pyroptosis host response |
| title | Dual role of TLR4 in bacterial meningitis through regulating endothelial pyroptosis and inflammatory response during extraintestinal pathogenic Escherichia coli infection |
| title_full | Dual role of TLR4 in bacterial meningitis through regulating endothelial pyroptosis and inflammatory response during extraintestinal pathogenic Escherichia coli infection |
| title_fullStr | Dual role of TLR4 in bacterial meningitis through regulating endothelial pyroptosis and inflammatory response during extraintestinal pathogenic Escherichia coli infection |
| title_full_unstemmed | Dual role of TLR4 in bacterial meningitis through regulating endothelial pyroptosis and inflammatory response during extraintestinal pathogenic Escherichia coli infection |
| title_short | Dual role of TLR4 in bacterial meningitis through regulating endothelial pyroptosis and inflammatory response during extraintestinal pathogenic Escherichia coli infection |
| title_sort | dual role of tlr4 in bacterial meningitis through regulating endothelial pyroptosis and inflammatory response during extraintestinal pathogenic escherichia coli infection |
| topic | bacterial meningitis toll-like receptor 4 blood-brain barrier endothelial pyroptosis host response |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1581696/full |
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