TLR4 signaling drives tissue inflammation, Claudin-5 internalization, and vascular barrier breakdown in a mouse model of neonatal meningitis

Neonatal bacterial meningitis poses a significant threat to infant health and survival, yet the underlying mechanisms of the leptomeningeal response to infection are not well understood. To investigate the role of Toll-like receptor 4 (TLR4) signaling in this context, researchers utilized a mouse model of neonatal Escherichia coli meningitis, employing conditional gene knockouts, leptomeningeal single-nucleus RNA sequencing, and endothelial cell culture.

Their findings reveal that TLR4 deletion in non-myeloid cells significantly reduced the inflammatory response across all leptomeningeal cell types and halted the associated increase in vascular permeability. Additionally, exposure of brain endothelial cells (bEnd.3 cells) to E. coli led to NF-κB activation, selective internalization of Claudin-5, and an increase in monolayer permeability—responses that were eliminated by Tlr4 knockout.

RNA sequencing demonstrated that TLR4 controls an NF-κB-driven transcriptional program orchestrating the endothelial response to E. coli. These results elucidate multiple TLR4-dependent host responses to neonatal Gram-negative bacterial meningitis.