Plasma-derived extracellular vesicles prime alveolar macrophages for autophagy and ferroptosis in sepsis-induced acute lung injury.

Summary

Plasma EV profiling identified a biomarker panel linked to sepsis severity and prognosis, with LCN2, miR-122-5p, and miR-223-3p independently predicting septic ARDS. Mechanistically, EV miR-223-3p activates Hippo signaling via MEF2C in alveolar macrophages, driving inflammation, autophagy, and ferroptosis; its inhibition attenuated lung injury in vivo.

Key Findings

• EV-based biomarker panel (miR-122-5p, miR-125b-5p, miR-223-3p, OLFM4, LCN2) correlated with sepsis severity/prognosis.
• LCN2, miR-122-5p, and miR-223-3p independently predicted septic ARDS.
• EV miR-223-3p promoted inflammation, autophagy, and ferroptosis in alveolar macrophages via MEF2C/Hippo signaling.
• Inhibition of miR-223-3p reduced lung inflammation, AM death, and histologic injury in vivo.

Clinical Implications

EV miR-223-3p and LCN2 could support early identification of patients at risk for septic ARDS and guide monitoring. Therapeutic inhibition of miR-223-3p warrants translational evaluation.

Limitations

• Clinical cohort size/details not fully specified; external validation cohorts not described
• LPS-based models may not recapitulate polymicrobial sepsis complexity

Future Directions

Prospectively validate EV biomarker thresholds for ARDS prediction and evaluate miR-223-3p-targeted therapeutics in clinically relevant sepsis models (e.g., CLP).