DLL4+ neutrophils promote Notch1-mediated endothelial PANoptosis to exacerbate acute lung injury in sepsis.
Summary
The study identifies DLL4+ neutrophils as drivers of Notch1-dependent endothelial PANoptosis in sepsis-induced ALI. A novel Notch1–DLL4 inhibitory peptide reduced endothelial PANoptosis, lung injury, inflammation, vascular leak, and improved survival in sepsis models.
Key Findings
- eCIRP induces DLL4+ neutrophils that drive ZBP1-initiated endothelial PANoptosis in sepsis.
- DLL4 binds Notch1 on pulmonary endothelium to activate Notch1 intracellular signaling and amplify ZBP1-mediated PANoptosis.
- A novel Notch1–DLL4 inhibitor (NDI) reduced endothelial PANoptosis, decreased lung injury and permeability, lowered inflammatory markers, and improved survival.
Clinical Implications
While preclinical, targeting Notch1–DLL4 signaling could inform future trials for sepsis-induced acute lung injury by preventing endothelial PANoptosis and barrier failure.
Why It Matters
Reveals a previously unrecognized neutrophil–endothelium pathway and provides a tractable therapeutic inhibitor with in vivo efficacy. This mechanistic advance opens a path to targeted therapies for sepsis-induced lung injury.
Limitations
- Preclinical models may not fully recapitulate human sepsis heterogeneity.
- Pharmacokinetics, safety, and dosing of the inhibitor in large animals/humans are not assessed.
Future Directions
Evaluate NDI pharmacology and safety, assess biomarkers of DLL4+ neutrophils/PANoptosis in patients, and design early-phase trials targeting Notch1–DLL4 in sepsis-induced ALI.
Study Information
- Study Type
- Case-control
- Research Domain
- Pathophysiology
- Evidence Level
- V - Preclinical mechanistic evidence from cellular and animal models without human intervention.
- Study Design
- OTHER