Dopamine signaling reprograms macrophage FAO to alleviate acute lung injury by inhibiting NETosis via the CXCL10-CXCR3 axis.

Summary

The study identifies accelerated dopamine turnover in ALI and demonstrates that D1-like receptor signaling reprograms macrophages to increase CPT1A-dependent fatty-acid oxidation and mitochondrial fitness, suppress MAPK/NF-κB and NLRP3 activation, and promote IL-10 secretion that inhibits the CXCL10–CXCR3 axis to reduce neutrophil hyperactivation and NETosis. This mechanism is conserved in human macrophages from ARDS patients, suggesting dopaminergic signaling as a therapeutic target.

Key Findings

• ALI is associated with accelerated dopamine turnover by public database and experimental evidence.
• D1-like receptor signaling increases CPT1A-dependent fatty-acid oxidation and mitochondrial fitness in macrophages, suppressing MAPK/NF-κB and NLRP3 activation.
• Reprogrammed macrophages secrete IL-10, inhibit CXCL10–CXCR3 signaling, reduce neutrophil hyperactivation and NETosis; effects conserved in human macrophages from ARDS patients.

Clinical Implications

Identifies dopamine signaling and metabolic reprogramming of macrophages as a potential therapeutic target to limit neutrophil-driven injury in ALI/ARDS; supports exploring dopaminergic agonists, CPT1A modulation, or IL-10–centric strategies in preclinical/early-phase trials.

Limitations

• Although human macrophages were studied, in vivo therapeutic efficacy and safety of manipulating dopaminergic signaling in ARDS patients remain untested.
• Dose, timing, and off-target effects of potential dopaminergic interventions require careful preclinical toxicology and pharmacology studies.

Future Directions

Preclinical studies to test dopaminergic agonists or CPT1A modulators in ARDS models with dosing/timing optimization, followed by early-phase clinical trials; biomarker development (TTV? cytokine signatures) to select responsive patients.