Macrophage-derived NPS drives acute lung injury by inducing CaMKII/NFATc3-Mediated M1 polarization

Acute lung injury (ALI), a major cause of mortality due to its frequent progression to acute respiratory distress syndrome (ARDS), is characterized by uncontrolled pulmonary inflammation. Given the limited efficacy of current clinical interventions, identifying novel therapeutic targets for ALI is imperative. Neuropeptide S (NPS) signals through its receptor (NPSR), a genetically validated asthma susceptibility factor that drives inflammatory pathogenesis. However, their role in ALI remains undefined. Given the limited efficacy of current treatments, identifying novel therapeutic targets is imperative. Although the neuropeptide S (NPS)-NPS receptor (NPSR) system is a genetically validated susceptibility factor in asthma, its role in ALI remains unknown. Here, we demonstrate that NPS and NPSR expression is significantly elevated in lung tissues and macrophages in a murine LPS-induced ALI model. Mechanistically, LPS promotes NPS production and upregulates NPSR expression in macrophages by activating NF-κB signaling, which directly binds to the NPS promoter. Functionally, NPS drives dose-dependent M1 polarization via calcium-dependent CaMKII/NFATc3 pathway, thereby exacerbating pulmonary inflammation and injury. Conversely, either pharmacological inhibition of NPSR or genetic ablation of NFATc3 abolishes NPS-induced M1 polarization and ameliorates LPS-triggered lung injury. Collectively, our findings identify macrophage-derived NPS as a key regulator of ALI pathogenesis that promotes M1 polarization through the CaMKII/NFATc3 axis, suggesting targeted inhibition of the NPS-NPSR pathway as a potential therapeutic strategy for ALI/ARDS.