Endothelial TREM-1 mediates sepsis-induced blood‒brain barrier disruption and cognitive impairment via the PI3K/Akt pathway.
Summary
Using iPSC-derived BBB and CLP sepsis models, the study shows endothelial TREM-1 upregulation drives BBB disruption and cognitive impairment via PI3K/Akt signaling. Endothelial-specific TREM-1 knockout preserved BBB integrity and cognition, and PI3K inhibition abrogated the protective effects of TREM-1 inhibition.
Key Findings
- Sepsis patient serum disrupts structure and function of iPSC-derived BBB
- Endothelial TREM-1 expression is upregulated in BBB models and CLP mice
- Endothelial-specific TREM-1 knockout attenuates BBB dysfunction and cognitive impairment
- PI3K/Akt signaling mediates TREM-1 effects; PI3K inhibition abolishes protection from TREM-1 inhibition
Clinical Implications
Endothelial TREM-1 and PI3K/Akt signaling represent candidate targets to preserve BBB integrity and mitigate cognitive sequelae in sepsis; biomarkers of endothelial activation could enable stratification for neuroprotective interventions.
Why It Matters
Identifies a tractable endothelial target and pathway for sepsis-associated encephalopathy, linking patient-derived stimuli to in vivo cognitive outcomes.
Limitations
- Preclinical models; lack of human interventional data
- Quantitative sample sizes and reproducibility across laboratories not detailed
Future Directions
Develop and test endothelial TREM-1 inhibitors or modulators in large-animal models and early-phase trials; evaluate circulating markers of endothelial TREM-1 activation for patient stratification in SAE.
Study Information
- Study Type
- Case-control
- Research Domain
- Pathophysiology
- Evidence Level
- V - Preclinical mechanistic evidence in cellular and animal models
- Study Design
- OTHER