Activated Notch1 promotes macrophage polarization and exacerbates sepsis-induced acute lung injury via β-catenin/NF-κB signaling.

Sepsis-induced acute lung injury (ALI) is a critical condition characterized by excessive inflammation, with macrophage polarization playing a pivotal role in its pathogenesis. In this study, we constructed myeloid-specific Notch1 knockout mice, overexpressed the Notch intracellular domain (NICD), and inhibited β-catenin using XAV939 to investigate the impact and mechanisms of Notch1 regulation in macrophage polarization and inflammatory responses in cecal ligation and puncture (CLP)-induced septic mice. The results demonstrated that Notch1 knockout significantly reduced M1 macrophage polarization, alleviated systemic inflammation, mitigated lung injury, and improved survival in septic mice. In sepsis, Notch1 enhances β-catenin expression, which synergizes with the NF-κB pathway to promote M1 polarization and pro-inflammatory cytokine production. Specifically, NICD interacts with β-catenin in macrophages, amplifying NF-κB activation and its nuclear translocation. These results demonstrate that the Notch1 signaling pathway plays a pivotal role in regulating macrophage phenotypic switching, highlighting its potential as a therapeutic target for attenuating sepsis-associated ALI through immune homeostasis restoration.