The pyroptosis cascade between inflammatory endothelial cells and microglia facilitates BBB disruption in bacterial meningitis.

Neonatal meningitis-causing Escherichia coli (NMEC) is a primary etiological agent of neonatal meningitis. Inflammatory cell death triggered by NMEC infection has been implicated as a critical determinant of blood-brain barrier (BBB) disruption and neuroinflammation. However, the mechanisms underlying inflammatory BBB breakdown and the propagation of inflammation within the neuroinflammatory milieu remain poorly understood. Here, we show that brain endothelial cells (ECs) undergo GSDMD-dependent pyroptosis in response to NMEC infection. Through integrated spatiotemporal single-cell transcriptomic, epigenomic, and proteomic analyses, we identify Gbp5 as a key regulator of pyroptosis in brain ECs. Moreover, we uncovered a homeostasis-to-inflammation transition in both ECs and microglia (MG), whereby pyroptotic ECs promote microglial pyroptosis via Angptl4-Sdc4 signaling. This intercellular communication establishes a "pyroptosis cascade" between BBB ECs and microglia in the central nervous system (CNS), providing mechanistic insight into inflammatory BBB disruption and revealing potential therapeutic targets within the CNS immune microenvironment.