IL-36 activates neutrophil extracellular traps and exacerbates LPS-induced ARDS in mice.

Summary

In a murine LPS-induced ARDS model, IL-36 administration increased pulmonary edema, inflammatory cytokines, histologic injury, and NET markers (CitH3, NE); IL-36 receptor antagonist attenuated these effects. NETs amplified IL-36-driven NF-κB phosphorylation and cytokine production in airway epithelial cells, suggesting IL-36 → NETs → NF-κB axis worsens ARDS.

Key Findings

• IL-36 administration in LPS-induced ARDS increased pulmonary edema, inflammatory cytokines (including TNF-α, MPO changes), and histopathologic lung injury.
• IL-36 promoted NETs formation evidenced by elevated citrullinated histone H3 (CitH3) and neutrophil elastase (NE).
• NETs amplified IL-36-induced NF-κB (p65) phosphorylation in bronchial epithelial cells; IL-36 receptor antagonist (IL-36Ra) partially reversed these effects.

Clinical Implications

Although preclinical, results nominate IL-36 signaling (or NET inhibition) as candidate therapeutic strategies to test in translational studies for sepsis-related ARDS; biomarkers (CitH3) may help stratify patients for targeted interventions.

Limitations

• Murine model may not fully recapitulate human sepsis-ARDS immunopathology; translational relevance requires validation in human samples.
• Detailed sample sizes and power calculations not reported in abstract; dose–response and timing of IL-36/IL-36Ra need further characterization.

Future Directions

Validate IL-36 and NET markers in human sepsis-ARDS cohorts; test IL-36 or NET-targeted interventions in larger preclinical models and early-phase clinical trials; elucidate cellular sources of IL-36 in lung injury.