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Background <p>Dysregulated innate immunity and oxidative stress drive the pathogenesis of acute lung injury/acute respiratory distress syndrome (ALI/ARDS), yet master endogenous regulators that orchestrate inflammation resolution remain elusive.</p> Methods <p>This study employed public database mining, clinical data investigation, murine disease models, mouse bone marrow-derived macrophages and neutrophils, and human macrophages from healthy donors and ARDS patients, to investigate the dynamic changes of the dopaminergic signaling system in the acute pulmonary inflammatory environment and its role in regulating macrophage metabolism and neutrophil extracellular trap formation (NETosis).</p> Results <p>Public database mining and experimental data reveal accelerated dopamine (DA) turnover during ALI. DA, signaling via D1-like receptors, reprograms macrophage metabolism by enhancing carnitine palmitoyltransferase 1&#xa0;A (CPT1A)-dependent fatty acid oxidation (FAO) and mitochondrial fitness, which is coupled with the suppression of MAPK/NF-κB and NLRP3 inflammasome activation. These modulated macrophages restrain neutrophilic inflammation by secreting IL-10 to inhibit the CXCL10-CXCR3 axis, thereby curtailing neutrophil hyperactivation and pathogenic NETosis. Crucially, this protective mechanism is conserved in human macrophages from both healthy donors and ARDS patients.</p> Conclusion <p>Our findings establish DA as a therapeutic target for recalibrating innate immunity in ALI, providing a mechanistically grounded framework for targeting dopaminergic signaling to resolve dysregulated inflammation, with exploratory preclinical translational implications for ALI/ARDS therapy.</p> Graphical abstract <p></p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月4日

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  • Ximing Liao,
  • Changwen Deng,
  • Jing Gao,
  • Ziqi Yang,
  • Tian Li,
  • Jialin Yao,
  • Muyun Wang,
  • Fengyang Xie,
  • Zhaoqi Li,
  • Kun Wang,
  • Qiang Li,
  • Di Wu,
  • Wujian Xu,
  • Wei Gao

摘要

Background

Dysregulated innate immunity and oxidative stress drive the pathogenesis of acute lung injury/acute respiratory distress syndrome (ALI/ARDS), yet master endogenous regulators that orchestrate inflammation resolution remain elusive.

Methods

This study employed public database mining, clinical data investigation, murine disease models, mouse bone marrow-derived macrophages and neutrophils, and human macrophages from healthy donors and ARDS patients, to investigate the dynamic changes of the dopaminergic signaling system in the acute pulmonary inflammatory environment and its role in regulating macrophage metabolism and neutrophil extracellular trap formation (NETosis).

Results

Public database mining and experimental data reveal accelerated dopamine (DA) turnover during ALI. DA, signaling via D1-like receptors, reprograms macrophage metabolism by enhancing carnitine palmitoyltransferase 1 A (CPT1A)-dependent fatty acid oxidation (FAO) and mitochondrial fitness, which is coupled with the suppression of MAPK/NF-κB and NLRP3 inflammasome activation. These modulated macrophages restrain neutrophilic inflammation by secreting IL-10 to inhibit the CXCL10-CXCR3 axis, thereby curtailing neutrophil hyperactivation and pathogenic NETosis. Crucially, this protective mechanism is conserved in human macrophages from both healthy donors and ARDS patients.

Conclusion

Our findings establish DA as a therapeutic target for recalibrating innate immunity in ALI, providing a mechanistically grounded framework for targeting dopaminergic signaling to resolve dysregulated inflammation, with exploratory preclinical translational implications for ALI/ARDS therapy.

Graphical abstract