CCR5+ NK cells drive hypoxemia in endotoxin-induced acute lung injury.

Summary

Using knockout, pharmacologic inhibition, and adoptive transfer in an endotoxin ALI mouse model, the study shows CCR5+ NK cells are causal drivers of hypoxemia and tissue injury. CCR5 blockade reduced NK trafficking and ameliorated lung injury, with efficacy even when initiated 2 hours post-LPS, highlighting a targetable pathway for ARDS endotypes.

Key Findings

• CCR5 ligands and CCR5+ NK cells increase in endotoxin-induced ALI compared with controls.
• CCR5 inhibition reduces NK cell trafficking in bronchoalveolar lavage and ameliorates lung injury across domains.
• Adoptive transfer of Ccr5-null NK cells diminishes trafficking and injury versus wildtype NK cells.
• NK cell depletion and CCR5 inhibition remain effective when administered 2 hours after LPS; T-cell trafficking is less affected.

Clinical Implications

Supports exploration of CCR5 antagonists (e.g., repurposing) for selected ARDS endotypes where NK cell-driven injury predominates, and encourages immune phenotyping to guide targeted therapy.

Limitations

• Endotoxin ALI may not fully recapitulate human ARDS heterogeneity.
• Lack of human validation and limited assessment of off-target effects of CCR5 inhibitors.

Future Directions

Validate CCR5-NK signatures in human ARDS cohorts; test approved CCR5 antagonists in relevant preclinical viral/bacterial ARDS models; define biomarkers to select responsive endotypes.