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

Yangyang Zheng1, Zhiyue Wu1, Fei Wu1

  • 1State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China; Tianjin Institutes of Health Science, Tianjin 301600, China.

Cell Reports
|June 30, 2026
PubMed

Insights

Neonatal meningitis-causing Escherichia coli triggers brain endothelial cell pyroptosis, leading to blood-brain barrier disruption. This study identifies a pyroptosis cascade involving microglia, offering new therapeutic targets for meningitis.

Area of Science:

  • Neuroscience
  • Immunology
  • Microbiology

Background:

  • Neonatal meningitis-causing Escherichia coli (NMEC) is a major cause of neonatal meningitis.
  • NMEC infection induces inflammatory cell death, crucial for blood-brain barrier (BBB) disruption and neuroinflammation.
  • Mechanisms of BBB breakdown and inflammation propagation in the CNS remain unclear.

Purpose of the Study:

  • To elucidate the mechanisms of NMEC-induced BBB disruption and neuroinflammation.
  • To identify key regulators of inflammatory cell death in brain endothelial cells (ECs).
  • To uncover intercellular communication pathways driving the neuroinflammatory cascade.

Main Methods:

  • Integrated spatiotemporal single-cell transcriptomic, epigenomic, and proteomic analyses.
  • Investigation of GSDMD-dependent pyroptosis in brain ECs following NMEC infection.
  • Analysis of intercellular signaling between ECs and microglia (MG).

Main Results:

  • Brain ECs undergo GSDMD-dependent pyroptosis upon NMEC infection.
  • Gbp5 was identified as a critical regulator of pyroptosis in brain ECs.
  • A pyroptosis cascade was uncovered, where pyroptotic ECs promote microglial pyroptosis via Angptl4-Sdc4 signaling.

Conclusions:

  • NMEC infection triggers a pyroptosis cascade between brain ECs and microglia.
  • This cascade contributes to BBB disruption and neuroinflammation in the CNS.
  • The identified signaling pathway presents potential therapeutic targets for neonatal meningitis.
Keywords:
BBB disruptionCP: immunologyCP: neuroscienceendothelial cellmicroglianeonatal meningitis-causing Escherichia colipyroptosis cascade

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