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Updated: Sep 19, 2025
Robust Ligature-Induced Model of Murine Periodontitis for the Evaluation of Oral Neutrophils
Published on: January 21, 2020
Pexidartinib Inhibits Macrophage Senescence Through Glycolysis in Periodontitis Microenvironment
Jifan Zhan1, Jiabing Kang2, Yan Wei3
1The Stomatology of Guizhou Medical University, Guizhou Medical University, Guiyang, China; Postgraduate Research Institute, Kunming Medical University, Kunming, China.
Objectives:
Periodontitis, a chronic inflammatory condition, is caused by complex interactions between periodontopathic bacteria and the local innate immune response. Macrophage senescence, a pivotal contributor to immune dysfunction, has been implicated in periodontitis progression. This research was conducted to clarify how macrophage senescence and glycolysis interact within the periodontal inflammatory microenvironment. Specifically, we investigated whether pexidartinib (PLX3397), known for inhibiting the colony-stimulating factor-1 receptor (CSF-1R), could mitigate macrophage senescence by modulating glycolytic activity, thereby attenuating periodontal inflammation.
Methods:
We first constructed the experiential periodontitis mouse model. The alveolar bone volume was quantified using Micro-CT, while the periodontal ligament width and the distance from the cementoenamel junction (CEJ) to the alveolar bone crest (ABC) were evaluated using HE staining. The expression levels of macrophage senescence markers, glycolysis-related indicators, and CSF-1R in gingival tissues were assessed by immunofluorescence staining. For in vitro studies, Senescence was induced in RAW264.7 cells by stimulating them with Porphyromonas gingivalis lipopolysaccharide (Pg-LPS) with or without pretreatment of PLX3397 and glycolysis modulators. Cellular senescence rates were evaluated using Senescence-associated β-Galactosidase (SA-β-Gal) staining. The presence of markers indicating senescence, CSF-1R, and glycolysis-related indicators was further analysed by RT-qPCR and Western blotting.
Results:
The gingival tissues of mice with periodontitis showed elevated senescent macrophages, which correlated with higher CSF-1R expression and glycolytic activity. Similarly, in Pg-LPS-treated RAW264.7 macrophages, senescence markers were upregulated alongside CSF-1R and glycolysis-related indicators. Meanwhile, modulating glycolysis in vitro directly influences senescence indicators. And PLX3397 treatment reduced glycolytic activity, leading to an improvement in macrophage senescence.
Conclusion:
Our findings indicate that PLX3397 alleviates periodontal tissue inflammation by inhibiting macrophage senescence via glycolytic modulation, offering potential for immune-regulatory therapies in periodontitis management.
Insights
Pexidartinib (PLX3397) reduces periodontal inflammation by targeting senescent macrophages. This drug inhibits colony-stimulating factor-1 receptor (CSF-1R), modulating glycolytic activity to lessen macrophage senescence and improve immune response in periodontitis.
Area of Science:
- Immunology
- Oral Biology
- Cellular Biology
Background:
- Periodontitis is a chronic inflammatory disease driven by bacterial infection and host immune responses.
- Macrophage senescence, a state of irreversible cell cycle arrest, contributes to immune dysfunction and periodontitis progression.
- The interplay between macrophage senescence and cellular metabolism, particularly glycolysis, in the periodontal microenvironment is not fully understood.
Purpose of the Study:
- To investigate the relationship between macrophage senescence and glycolysis in periodontitis.
- To evaluate the efficacy of pexidartinib (PLX3397), a colony-stimulating factor-1 receptor (CSF-1R) inhibitor, in mitigating macrophage senescence and periodontal inflammation.
Main Methods:
- Established an experimental periodontitis mouse model, assessing alveolar bone loss and periodontal tissue damage.
- Analyzed macrophage senescence markers, glycolysis indicators, and CSF-1R expression in gingival tissues using immunofluorescence, RT-qPCR, and Western blotting.
- Induced macrophage senescence in vitro using Porphyromonas gingivalis lipopolysaccharide (Pg-LPS) and treated with PLX3397 or glycolysis modulators, assessing senescence via SA-β-Gal staining.
Main Results:
- Periodontitis in mice and Pg-LPS-treated macrophages exhibited increased senescent macrophages, elevated CSF-1R expression, and heightened glycolytic activity.
- In vitro modulation of glycolysis directly impacted senescence markers in macrophages.
- PLX3397 treatment effectively reduced glycolytic activity, thereby ameliorating macrophage senescence.
Conclusions:
- PLX3397 alleviates periodontal inflammation by inhibiting macrophage senescence through the modulation of glycolytic pathways.
- Targeting macrophage senescence via CSF-1R inhibition and glycolytic modulation presents a potential therapeutic strategy for periodontitis management.
