Neutrophils suppress osteogenic differentiation of Gli1+ stem cells via neutrophil extracellular traps and contribute to bone loss in periodontitis

Periodontitis is a severe and chronic oral inflammatory disease that leads to the progressive and irreversible destruction of periodontal tissues, ultimately resulting in tooth loss. Among the immune cell subtypes involved, neutrophils play a crucial role in the initiation and progression of periodontitis. Mesenchymal stem cells (MSCs) are essential components of periodontal tissue, contributing to tissue development, homeostasis, and regeneration. Recent studies have demonstrated that neutrophils significantly affect the function of MSCs by changing the inflammatory environment. However, the specific effects of neutrophils on periodontal MSCs during periodontitis remain unclear, highlighting a gap in our understanding of the disease mechanisms. In this study, we utilized the Gli1-CreER^T2;mT/mG transgenic mouse model to specifically mark Gli1⁺ cells, a critical and representative subset of MSCs in the periodontal tissues responsible for maintaining tissue homeostasis. We reveal that neutrophils inhibit the osteogenic differentiation of Gli1⁺ cells and exacerbate alveolar bone destruction by secreting neutrophil extracellular traps (NETs), which induce endoplasmic reticulum stress in Gli1⁺ cells. These findings highlight the pivotal impact of neutrophils on distinct subpopulations of periodontal MSCs in the pathogenesis of periodontitis, offering valuable insights into the underlying mechanisms of the disease and suggesting potential future therapeutic strategies aimed at modulating the interactions between neutrophils and MSCs.