CSF1R inhibitor (PLX3397) alleviates experimental periodontitis by reducing macrophage senescence through the PI3K/AKT/FOXO1 signaling pathway.

Macrophage senescence is closely associated with the progression of periodontitis. In vitro investigations have demonstrated that the colony-stimulating factor 1 receptor (CSF1R) inhibitor, PLX3397, reduces macrophage senescence; however, the underlying mechanisms remain unclear. This study explored whether CSF1R inhibitors mitigate periodontitis by reducing macrophage senescence and examined the role of the PI3K/AKT/FOXO1 signaling pathway. Using C57BL/6 mice and RAW264.7 cells, periodontal tissues were analyzed with Micro-CT, hematoxylin and eosin staining, immunofluorescence, and immunohistochemistry. Senescence-associated-β-galactosidase staining, RT-qPCR, and western blotting assessed cellular senescence, while reactive oxygen species (ROS) levels were measured by flow cytometry. Our findings revealed that PLX3397 significantly reduced periodontal tissue destruction and inflammation, and decreased the number of senescent macrophages in a murine periodontitis model. In Porphyromonas gingivalis-lipopolysaccharide-stimulated RAW264.7 macrophages, PLX3397 reduced macrophage senescence via PI3K/AKT/FOXO1 signaling and downregulated ROS expression. These findings demonstrate that CSF1R inhibitors effectively mitigate periodontitis by targeting macrophage senescence through the PI3K/AKT/FOXO1 pathway, providing potential therapeutic insights for periodontitis.