Investigation of the correlation between Notch signaling mediated Jagged1 and inflammatory responses in innate immune cells

The Notch signaling pathway is vital for cell development and immune system function. Mutations in the Jagged1 (JAG1) ligand of this pathway lead to Alagille syndrome (AGS), a pediatric genetic disorder causing bile duct reduction and organ abnormalities. However, it remains unknown whether JAG1-mediated Notch signaling regulates inflammatory responses in innate immune cells. Here, we investigated the correlation between impaired Notch signaling mediated by the mutated JAG1 and inflammatory responses in innate immune cells. We explored three different missense mutations in AGS cases to analyze their functional abnormality regarding JAG1 cell-surface localization, post-translational modification, and Notch signaling ability. The pathogenic variants correlated closely with pro-inflammatory cytokines. Furthermore, we investigated the functional effect of JAG1 missense mutations on innate immune cells in vivo. In JAG1-null mice, multiple organ dysfunction manifested, especially in the liver. JAG1 deficiency stimulated pro-inflammatory cytokine secretion and M1 macrophage polarization, aggravating liver damage via hyper-macrophage extracellular traps and potentially inducing biliary sepsis. Understanding how JAG1/Notch signaling abnormalities affect innate immune cells provides a basis for developing therapeutic strategies for Notch signaling-related diseases and innate immune response abnormalities caused by JAG1-mediated Notch signaling.