Extracellular peroxiredoxin 6 released from alveolar epithelial cells as a DAMP drives macrophage activation and inflammatory exacerbation in acute lung injury.

Summary

Prospective human data and mechanistic experiments identify extracellular PRDX6 as a DAMP in ALI/ARDS. PRDX6 binds MD2 to activate TLR4/NF-κB, drives macrophage M1 polarization, and correlates with worse prognosis; blocking TLR4–MD2 attenuates inflammation.

Key Findings

• BAL PRDX6 levels were elevated in ARDS and correlated with monocytic activation and poor prognosis.
• Alveolar epithelial cells actively released PRDX6 under stress in vitro and in murine acute lung injury in vivo.
• Exogenous PRDX6 activated TLR4/NF-κB signaling, inducing macrophage M1 polarization; TLR4–MD2 inhibition mitigated inflammation.
• Molecular docking and binding assays showed direct PRDX6–MD2 interaction, supporting a DAMP role.

Clinical Implications

PRDX6 in BAL may serve as a biomarker of inflammatory burden and a potential target; pharmacologic disruption of PRDX6–MD2/TLR4 could mitigate lung inflammation in ARDS.

Limitations

• Human sample size and detailed cohort characteristics not reported in abstract
• Causality in humans is inferred; translational efficacy of pathway inhibition remains untested clinically

Future Directions

Quantify PRDX6 prognostic performance in multi-center ARDS cohorts and develop/assess MD2–TLR4 pathway inhibitors or PRDX6-neutralizing strategies in translational models.