{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T04:07:17Z","timestamp":1790482037792,"version":"4.1.0"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,3,18]],"date-time":"2025-03-18T00:00:00Z","timestamp":1742256000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Multiple sclerosis (MS) is characterized by chronic inflammation and demyelination within the central nervous system (CNS), primarily driven by the abnormal activation of the peripheral immune system, notably Th1 cells. As the principal pathogen in periodontitis, <jats:italic>Porphyromonas gingivalis<\/jats:italic> (<jats:italic>P. gingivalis<\/jats:italic>) is linked to an increased risk of multiple sclerosis progression; however, its role in central nervous system inflammation remains unclear. In this study, we aimed to determine whether <jats:italic>P. gingivalis<\/jats:italic> promotes peripheral Th1 cell differentiation via the ZAP70\/NF-\u03baB signaling pathway, thereby exacerbating experimental autoimmune encephalomyelitis(EAE), a model of multiple sclerosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>C57BL\/6J mice were randomly divided into healthy control, periodontitis, EAE, and periodontitis with EAE group. Neurological function was assessed using Weaver\u2019s score. Histopathology (H&amp;amp;E, LFB staining) and Evans blue dye leakage evaluated inflammation, demyelination, and blood-brain barrier(BBB)permeability. Th1 and Th17 cells were quantified by flow cytometry, while immunofluorescence staining was performed to analyze Claudin-5, IFN-\u03b3 <jats:sup>+<\/jats:sup>CD4<jats:sup>+<\/jats:sup> T -positive cell and IL-17<jats:sup>+<\/jats:sup>CD4<jats:sup>+<\/jats:sup>-positive cell expression. Western blotting measured NF-\u03baB and related protein expression. Reference-based mRNA sequencing analysis and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment was conducted to identify differential gene expression and pathway enrichment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In mice with experimental autoimmune encephalomyelitis, <jats:italic>P. gingivalis<\/jats:italic> infection significantly elevated Th1 cell proportions in the peripheral blood, increased interferon-gamma expression, and exacerbated central nervous system inflammation and demyelination by enhancing blood\u2013brain barrier permeability. The infection also activated the ZAP70\/NF-\u03baB pathway, essential for peripheral Th1 differentiation, as evidenced by p65 nuclear translocation and significant upregulation of Th1-related genes, including those of the transcription factor <jats:italic>Tbx21<\/jats:italic> and interleukin-12 receptors. <jats:italic>In vitro<\/jats:italic>, <jats:italic>P. gingivalis<\/jats:italic> lipopolysaccharide (LPS) stimulated Th1 differentiation via ZAP70\/NF-\u03baB, which was effectively blocked by pathway inhibitors, reducing Th1 cells and pro-inflammatory factors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Our findings elucidate, for the first time, how <jats:italic>P. gingivalis<\/jats:italic> infection promotes central nervous system inflammation by driving Th1 cell differentiation via peripheral ZAP70\/NF-\u03baB pathway activation. This highlights <jats:italic>P. gingivalis<\/jats:italic> as a local periodontitis pathogen and significant contributor to neuroinflammation, providing new insights into the pathogenesis of multiple sclerosis and identifying promising targets for immunomodulatory therapeutic strategies.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1549102","type":"journal-article","created":{"date-parts":[[2025,3,18]],"date-time":"2025-03-18T05:22:54Z","timestamp":1742275374000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Porphyromonas gingivalis exacerbates experimental autoimmune encephalomyelitis by driving Th1 differentiation via ZAP70\/NF-\u03baB signaling"],"prefix":"10.3389","volume":"16","author":[{"given":"Dong","family":"Dai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoqin","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengyuan","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jilei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuying","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiang","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,3,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.824411","article-title":"Astrocytes and inflammatory T helper cells: A dangerous liaison in multiple sclerosis","volume":"13","author":"Kunkl","year":"2022","journal-title":"Front Immunol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.996469","article-title":"Autoreactive lymphocytes in multiple sclerosis: pathogenesis and treatment target","volume":"13","author":"Liu","year":"2022","journal-title":"Front Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2020.26858","article-title":"Diagnosis and treatment of multiple sclerosis: A review","volume":"325","author":"McGinley","year":"2021","journal-title":"JAMA"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1002\/art.38007","article-title":"Interleukin-7 enhances the th1 response to promote the development of sjogren's syndrome-like autoimmune exocrinopathy in mice","volume":"65","author":"Jin","year":"2013","journal-title":"Arthritis Rheum"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-024-01901-1","article-title":"Bach2 regulates diversification of regulatory and proinflammatory chromatin states in T(H)17 cells","volume":"25","author":"Thakore","year":"2024","journal-title":"Nat Immunol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"2298","DOI":"10.1016\/j.cmet.2024.07.017","article-title":"Obesity intensifies sex-specific interferon signaling to selectively worsen central nervous system autoimmunity in females","volume":"36","author":"Cordeiro","year":"2024","journal-title":"Cell Metab"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2023.1101379","article-title":"The interplay between T helper cells and brain barriers in the pathogenesis of multiple sclerosis","volume":"17","author":"Angelini","year":"2023","journal-title":"Front Cell Neurosci"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2022.1019877","article-title":"Advantages and limitations of experimental autoimmune encephalomyelitis in breaking down the role of the gut microbiome in multiple sclerosis","volume":"15","author":"Melamed","year":"2022","journal-title":"Front Mol Neurosci"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2021.766944","article-title":"Periodontal disease: the good, the bad, and the unknown","volume":"11","author":"Sedghi","year":"2021","journal-title":"Front Cell Infect Microbiol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1186\/s12903-023-03846-7","article-title":"Exploration of potential shared gene signatures between periodontitis and multiple sclerosis","volume":"24","author":"Wu","year":"2024","journal-title":"BMC Oral Health"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1002\/JPER.17-0531","article-title":"Oral infection with P. 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