TLR4 signaling drives tissue inflammation, Claudin-5 internalization, and vascular barrier breakdown in a mouse model of neonatal meningitis
Related Experiment Video
Updated: Aug 20, 2026
A Murine Model of Fetal Exposure to Maternal Inflammation to Study the Effects of Acute Chorioamnionitis on Newborn Intestinal Development
Published on: June 24, 2020
Philip V Seegren1,2, Amir Rattner1,2, Philip M Smallwood1,2
1Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, United States.
Abstract:
Neonatal bacterial meningitis is a leading cause of infant morbidity and mortality, yet the molecular and cellular basis of the leptomeningeal response to infection remains poorly defined. Here, we study a mouse model of neonatal Escherichia coli meningitis, combining conditional gene knockouts, leptomeningeal single-nucleus RNA sequencing, and endothelial cell culture to explore the role of Toll-like receptor 4 (TLR4) signaling in the host response to infection. Deletion of Tlr4 in non-myeloid cells dramatically reduced the inflammatory response in all leptomeningeal cell types and abrogated the infection-associated increase in vascular permeability. In a brain endothelial cell line (bEnd.3 cells), exposure to E. coli triggered NF-κB activation, selective internalization of Claudin-5, and increased monolayer permeability, responses that were eliminated by Tlr4 knockout. RNA-seq showed that TLR4 controls an NF-κB-driven transcriptional program that orchestrates the endothelial response to E. coli. These findings reveal multiple TLR4-dependent host responses to neonatal Gram-negative bacterial meningitis.
Insights
Neonatal bacterial meningitis involves Toll-like receptor 4 (TLR4) in non-myeloid cells. Blocking TLR4 reduces inflammation and vascular permeability during E. coli meningitis in mice.
Area of Science:
- Neuroscience
- Immunology
- Microbiology
Background:
- Neonatal bacterial meningitis poses significant risks to infant health.
- The intricate cellular mechanisms of the leptomeningeal response to infection are not fully understood.
Purpose of the Study:
- To investigate the role of Toll-like receptor 4 (TLR4) signaling in the host's response to neonatal Gram-negative bacterial meningitis.
- To elucidate the molecular and cellular basis of the leptomeningeal response during infection.
Main Methods:
- Utilized a mouse model of neonatal Escherichia coli meningitis.
- Employed conditional gene knockouts, single-nucleus RNA sequencing of leptomeningeal cells, and endothelial cell cultures.
- Examined NF-κB activation and Claudin-5 internalization in brain endothelial cells.
Main Results:
- Deletion of Tlr4 in non-myeloid cells significantly diminished the inflammatory response across all leptomeningeal cell types.
- Tlr4 knockout abrogated infection-induced increases in vascular permeability.
- TLR4 was found to control an NF-κB-driven transcriptional program regulating the endothelial response to E. coli.
Conclusions:
- TLR4 signaling in non-myeloid cells is critical for orchestrating the host response to neonatal Gram-negative bacterial meningitis.
- TLR4 plays a key role in regulating brain endothelial cell responses, including vascular permeability and inflammatory signaling.
More Related Videos
Related Concept Videos
01:26Bacterial Meningitis II: Pathophysiology
01:25Inflammatory Bowel Disease III: Crohn's Disease