Dopamine signaling governs macrophage-mediated acute lung injury through JAML/IL-10-coupled mitochondrial regulation

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) remain devastating clinical entities characterized by uncontrolled pulmonary inflammation driven by dysregulated macrophage activation, with limited therapeutic options and high mortality. Emerging evidence implicates neuroimmune crosstalk as a pivotal regulator in inflammatory disorders, yet the role of dopaminergic signaling in orchestrating macrophage function during ALI remains ill-defined. Herein, we systematically characterized the dynamic perturbations of pulmonary dopaminergic signaling during ALI/ARDS progression and delineated the anti-inflammatory and cytoprotective properties of dopamine (DA) D1-like receptor (D1R) signaling in ALI mouse model and targeted macrophages. Mechanistically, DA-D1R activation mitigated macrophage hyperactivation by reversing lipopolysaccharide-induced mitochondrial dysfunction, thereby curbing excessive M1 polarization and maintaining cellular homeostasis. Transcriptomic profiling identified junctional adhesion molecule-like protein (JAML) as a critical downstream effector of the D1R agonist SKF38393 (SKF) in macrophages. SKF downregulated JAML expression and its interaction with interleukin (IL)-10, thus enhancing IL-10 bioavailability to sustain mitochondrial integrity and limit oxidative damage. Notably, the anti-inflammatory capacity of DA bioactivity system was validated in macrophages from ARDS patients and healthy controls, underscoring its translational potential. Collectively, our findings unravel a previously unrecognized DA-D1R-JAML/IL-10-mitochondria axis that governs macrophage-mediated ALI, positioning dopaminergic signaling as a promising therapeutic target for ARDS and other inflammatory disorders involving neuroimmune dysfunction.