Paraventricular nucleus CRH neurons regulate acute lung injury via sympathetic nerve-neutrophil axis

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are severe conditions with high morbidity and mortality with limited effective therapies. Neuroimmune interactions play a critical role in lung homeostasis, but it remains unclear if specific brain regions regulate lung inflammation. Here, we perform anatomical tracing, chemogenetic modulation, and pharmacological interventions in male mice and identify a neural circuit from corticotropin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus (CRH(PVN) neurons) to the lung. The activation of these neurons protects mice from ALI and promotes survival, reduces neutrophil infiltration and effector functions in the lung, whereas inhibiting CRH(PVN) neurons worsens ALI. The protective effect is mediated by increased sympathetic nervous activity, with locally released norepinephrine modulating neutrophil functions via β2-AR-β-arrestin2 signaling to inhibit the NF-κB pathway. These findings uncover a brain-lung neural circuit that modulates immune responses during ALI, offering a potential therapeutic target for ALI and ARDS.