XAV-939

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.

The role of T‐cell factor 1 (TCF1) in human regulatory T cells (Treg) and its clinical significance in systemic lupus erythematosus (SLE) remain unclear. Through bioinformatics analysis and flow cytometry, the Tcf7 gene and TCF1 protein were found to be highly expressed in Treg cells. TCF1+ Treg cells exhibited increased expression of CTLA4 and LAG3 and higher IL‐10 secretion than TCF1− Treg cells. Circulating TCF1+ Treg cells were elevated and displayed increased inhibitory markers in SLE patients. The Wnt‐β‐catenin pathway was activated in TCF1+ Treg cells in SLE patients. The addition of XAV939 impaired the function of TCF1+ Treg cells. Clinically, TCF1+ Treg cells were not only related to CRP, ESR and IL‐2, but also could differentiate SLE patients from healthy controls, primary Sjögren's syndrome patients and rheumatoid arthritis patients. In conclusion, the increased TCF1+ Treg cells in SLE patients indicate a stronger suppressive function for the activated Wnt‐β‐catenin pathway and help screening and assisting in the diagnosis of SLE patients.