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, and effective treatments are limited. Neuroimmune interactions play a critical role in lung homeostasis, but it remains unclear if specific brain regions regulate lung inflammation. Here, we unveil the critical role of neuroimmune signaling in ALI, focusing on the regulatory function of corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus (PVN) of the hypothalamus. Using viral tracing, chemogenetic modulation, and pharmacological interventions in mouse models of ALI induced by intranasal lipopolysaccharide and cecal ligation and puncture (CLP), we found that lung injury activated CRHPVN neurons that projected to the lung. Activation of these neurons protected mice from ALI and death, reducing neutrophil infiltration and effector functions in the lung. In contrast, inhibiting CRHPVN neurons exacerbated ALI. Notably, the beneficial impact of CRHPVN neuron activation is compromised by the pulmonary chemical sympathectomy or inhibition of the ß2-adrenergic receptor. These protective effects were dependent on sympathetic nerves, with norepinephrine released locally to modulate neutrophil functions via ß2-AR–ß-arrestin2 signaling, inhibiting the NF-?B pathway. Our findings reveal a brain-lung axis that regulates immune responses in ALI, suggesting novel therapeutic targets for ALI and ARDS. Overall design: CRH-IRES-Cre mice were injected with AAV2/9-Ef1a-DIO-mCherry (control group) or AAV2/9-Ef1a-DIO-hM3Dq-mCherry (experimental group) into the paraventricular nucleus (PVN). After viral expression, CNO was intraperitoneally injected, and 1 hour later, LPS (20 mg/kg) was administered intranasally to induce acute lung injury (ALI). Lung tissues were collected 8 hours post-LPS for RNA sequencing.