Single-Cell and Spatial Multi-Omics Analysis Reveal That Targeting JAG1 in Epithelial Cells Reduces Periodontal Inflammation and Alveolar Bone Loss

Abstract

Mucosal immunity plays a critical role in the pathogenesis of inflammatory immune diseases. This study leverages single-cell RNA sequencing, spatial transcriptomics, and spatial proteomics to compare the cellular mechanisms involved in periodontitis between humans and mice, aiming to develop precise strategies to protect the gingival mucosal barrier. We identified key conserved and divergent features in cellular landscapes and transcriptional profiles across the two species, underscoring the complexity of inflammatory responses and immune dynamics in periodontitis. Additionally, we revealed a novel regulatory mechanism by which epithelial cells modulate macrophage behavior and inflammation through the JAG1–Notch pathway. Validation through animal experiments revealed that JAG1 inhibition reduces inflammation in epithelial cells, mitigating periodontitis. Our findings advance the understanding of periodontal disease pathogenesis and highlight the importance of integrating human and animal model data to develop treatments aligned with human physiology, offering potential therapeutic targets for controlling inflammation and enhancing tissue regeneration.