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

Summary

Dopamine emerges as an endogenous regulator that shifts macrophages toward CPT1A-dependent fatty acid oxidation, dampening MAPK/NF-κB and NLRP3 signals. The resulting IL‑10–mediated suppression of the CXCL10–CXCR3 axis curtails neutrophil NETosis and alleviates acute lung injury, with conservation in human macrophages.

Key Findings

• ALI accelerates dopamine turnover; dopamine signaling via D1-like receptors enhances CPT1A-dependent FAO and mitochondrial fitness in macrophages.
• Dopamine suppresses MAPK/NF-κB and NLRP3 activation and increases IL‑10 secretion, which inhibits the CXCL10–CXCR3 axis.
• Limiting CXCL10–CXCR3 signaling restrains neutrophil hyperactivation and NETosis, alleviating lung injury in murine models.
• The protective mechanism is conserved in human macrophages from healthy donors and ARDS patients.

Clinical Implications

Selective D1-like receptor agonists or FAO-enhancing strategies could modulate macrophage reprogramming and reduce NETosis in ALI/ARDS; CXCL10–CXCR3 may serve as a pharmacodynamic biomarker.

Limitations

• Predominantly preclinical; clinical dosing, safety, and efficacy of dopaminergic modulation in ARDS remain untested.
• Systemic effects of dopamine/D1 agonism introduce potential hemodynamic confounding requiring careful study design.

Future Directions

Evaluate selective D1 agonists, CPT1A modulators, or CXCL10–CXCR3 inhibitors in ALI/ARDS models and early-phase trials; develop biomarkers to monitor immunometabolic reprogramming.