Stat3-mediated-Th17 pathogenicity induced by periodontitis contributes to cognitive impairment by promoting microglial M1 polarization

Yining Zhou¹Xinyi Xie^1,2Huiwen Chen¹Lina Xu¹Che Qiu¹Hui Shen¹Wei Zhou^1*Zhongchen Song^1*

• ¹Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
• ²Dental disease prevention and treatment center of Minhang District, Shanghai, China

Introduction: Periodontitis has been identified as a potential risk factor for cognitive impairment associated with immune dysregulation. Additionally, T helper 17 (Th17) cell-associated immune responses are involved in both diseases, while signal transducer and activator of transcription 3 (Stat3) is kown to be crucial for Th17 pathogenicity. Accordingly, in this study, we investigated how Stat3-mediated-Th17 pathogenicity contributes to the link between periodontitis and cognitive impairment. Methods: Levels of Th17-related cytokines in gingival crevicular fluid (GCF) were measured in individuals with and without cognitive impairment. A periodontitis model was established in mice with conditional deletion of Stat3 in Th17 cells (Stat3 fl/fl ; Il17a-CreERT2, cKO) and wild type (Stat3 fl/fl , WT) mice via injection of Porphyromonas gingivalis-lipopolysaccharide (P. gingivalis-LPS) into gingival sulcus. Cognitive function was assessed through behavioral tests. Expression of Th17-related cytokines and microglial pro-inflammatory markers was evaluated by reverse transcription-quantitative PCR (RT-qPCR), ELISA, flow cytometry, and immunohistochemistry. To evaluate effects of CD4 + T cells on microglial M1 polarization, BV2 microglia were cocultured with primary CD4 + T cells isolated from cKO and WT mice previously stimulated with P. gingivalis-LPS. Results: Compared with cognitively normal controls, levels of Th17-related cytokines increased in participants with cognitive impairment. Significant alveolar bone resorption and cognitive impairment were observed in WT mice with periodontitis. These periodontitis-induced changes were alleviated in cKO mice, accompanied by a weakening of neuroinflammation and mitigation of Th17 immune responses. In vitro, M1 polarization and activation of the MAPK/ERK signaling pathway were inhibited in BV2 cells co-cultured with Stat3-deleted Th17 cells. Conclusion: Stat3-mediated Th17 pathogenicity bridged the correlation between periodontitis and neuroinflammation related to cognitive impairment, offering novel perspectives for a therapeutic target for blocking the mouth-to-brain axis.