{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T17:15:17Z","timestamp":1793207717980,"version":"4.5.0"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,8,26]],"date-time":"2025-08-26T00:00:00Z","timestamp":1756166400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82071112, 82270974, 81971299"],"award-info":[{"award-number":["82071112, 82270974, 81971299"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2023YFC2506301"],"award-info":[{"award-number":["2023YFC2506301"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003399","name":"Science and Technology Commission of Shanghai Municipality","doi-asserted-by":"publisher","award":["22ZR1437500"],"award-info":[{"award-number":["22ZR1437500"]}],"id":[{"id":"10.13039\/501100003399","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Periodontitis has been identified as a potential risk factor for cognitive impairment associated with immune dysregulation. T helper 17 (Th17) cell-associated immune responses are involved in both diseases, while signal transducer and activator of transcription 3 (<jats:italic>Stat3<\/jats:italic>) is kown to be crucial for Th17 pathogenicity. Accordingly, in this study, we investigated how <jats:italic>Stat3<\/jats:italic>-mediated Th17 pathogenicity contributes to the link between periodontitis and cognitive impairment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>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 <jats:italic>Stat3<\/jats:italic> in Th17 cells (<jats:italic>Stat3<\/jats:italic><jats:sup>fl\/fl<\/jats:sup>; <jats:italic>Il17a-<\/jats:italic>CreERT2, cKO) and wild type (<jats:italic>Stat3<\/jats:italic><jats:sup>fl\/fl<\/jats:sup>, WT) mice via injection of <jats:italic>Porphyromonas gingivalis<\/jats:italic> lipopolysaccharide (<jats:italic>P. gingivalis<\/jats:italic> 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<jats:sup>+<\/jats:sup> T cells on microglial M1 polarization, BV2 microglia were co-cultured with primary CD4<jats:sup>+<\/jats:sup>T cells which were stimulated with <jats:italic>P. gingivalis<\/jats:italic> LPS after isolated from cKO and WT mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Compared with cognitively normal participants, 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. <jats:italic>In vitro<\/jats:italic>, M1 polarization and activation of the MAPK\/ERK signaling pathway were inhibited in BV2 cells co-cultured with <jats:italic>Stat3<\/jats:italic>-deleted Th17 cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p><jats:italic>Stat3<\/jats:italic>-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.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1590665","type":"journal-article","created":{"date-parts":[[2025,8,26]],"date-time":"2025-08-26T04:13:34Z","timestamp":1756181614000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Stat3-mediated Th17 pathogenicity induced by periodontitis contributes to cognitive impairment by promoting microglial M1 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