DLL4+ neutrophils promote Notch1-mediated endothelial PANoptosis to exacerbate acute lung injury in sepsis.
Summary
This mechanistic study identifies a DLL4+ neutrophil subset that engages endothelial Notch1 to induce ZBP1-driven PANoptosis, worsening sepsis-induced ALI. A novel Notch1-DLL4 inhibitor peptide reduced endothelial PANoptosis, lung injury, permeability, inflammatory markers, and improved survival in sepsis models, highlighting a druggable axis.
Key Findings
- eCIRP induces DLL4+ neutrophils that trigger ZBP1-mediated endothelial PANoptosis.
- DLL4 binds endothelial Notch1, activating Notch1 intracellular domain to amplify PANoptosis markers (cleaved GSDMD, cleaved caspase-3, p-MLKL).
- A Notch1-derived inhibitor (NDI) blocks DLL4–Notch1 interaction, reducing endothelial PANoptosis, lung injury, permeability, inflammatory markers, and improving survival in sepsis models.
Clinical Implications
Targeting the Notch1–DLL4 interaction may prevent or mitigate sepsis-associated acute lung injury. If translated, NDI-like agents could complement current supportive care by preserving endothelial barrier function.
Why It Matters
Reveals a previously unrecognized neutrophil–endothelial pathway driving ALI and demonstrates a first-in-class inhibitor that improves outcomes in preclinical sepsis.
Limitations
- Preclinical models; human validation of DLL4+ neutrophils and NDI efficacy/safety is lacking.
- Potential off-target effects of Notch pathway modulation require careful evaluation.
Future Directions
Validate DLL4+ neutrophils and PANoptosis signatures in human sepsis cohorts; optimize NDI pharmacology, safety, and delivery; explore combination with standard sepsis care.
Study Information
- Study Type
- Case-control
- Research Domain
- Pathophysiology
- Evidence Level
- V - Preclinical mechanistic study using cell and animal models; hypothesis-generating evidence.
- Study Design
- OTHER