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The Blood-brain Barrier00:49

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Brain endothelial GSDMD activation mediates inflammatory BBB breakdown.

Chao Wei1, Wei Jiang2,3, Ruiyu Wang2

  • 1Chinese Institute for Brain Research, Beijing, P. R. China.

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The blood-brain barrier (BBB) breaks down due to GSDMD activation in brain endothelial cells, triggered by lipopolysaccharide (LPS). This mechanism explains inflammatory BBB disruption and suggests new therapeutic targets.

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Area of Science:

  • Neuroscience
  • Immunology
  • Cell Biology

Background:

  • The blood-brain barrier (BBB) protects the central nervous system but its disruption contributes to neurological diseases.
  • Mechanisms of BBB breakdown during infection and inflammation are not well understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying BBB disruption in response to lipopolysaccharide (LPS) and sepsis.
  • To identify key cellular players and pathways involved in LPS-induced BBB breakdown.

Main Methods:

  • Utilized mouse models deficient in LPS transfer pathways and genetically engineered mice.
  • Performed single-cell RNA-sequencing, electron microscopy, and in vitro cell culture experiments.
  • Employed adeno-associated virus systems for targeted gene delivery in brain endothelial cells (bECs).

Main Results:

  • Activation of GSDMD by caspase-11, not TLR4-induced cytokines, mediates BBB breakdown in response to LPS.
  • Brain endothelial cells (bECs) expressing GSDMD are central to LPS-induced BBB disruption via pyroptosis.
  • Genetic ablation of LPS transfer pathways prevented BBB breakdown; GSDMD delivery alone disrupted the BBB.

Conclusions:

  • GSDMD activation in bECs is a critical mechanism for LPS-induced inflammatory BBB breakdown.
  • This pathway is conserved, as Gram-negative bacterial infection also triggers BBB disruption, preventable with GSDMD neutralization.
  • Findings offer potential therapeutic strategies for CNS diseases involving BBB impairment.