{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T08:53:31Z","timestamp":1773392011396,"version":"3.50.1"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T00:00:00Z","timestamp":1773360000000},"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. Neurosci."],"abstract":"\n Objective<\/jats:title>\n \n Chronic periodontitis is a significant risk factor for systemic disorders. However, the precise mechanism through which the \u201coral-brain axis\u201d mediates its impact on the central nervous system remains unclear. This study aimed to investigate whether the periodontal pathogen\n Porphyromonas gingivalis<\/jats:italic>\n (\n P. gingivalis<\/jats:italic>\n ) induces endothelial-mesenchymal transition (EndoMT), thereby disrupting the blood\u2013brain barrier (BBB) and triggering neuroinflammation, and to elucidate the regulatory role of the deubiquitinating enzyme USP22 in this process.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n A chronic oral infection model of\n P. gingivalis<\/jats:italic>\n was established in mice, which was confirmed by assessing inflammatory factor levels in periodontal tissues. Endothelial tight junction proteins (ZO-1 and Claudin-5), a mesenchymal marker (\n \u03b1<\/jats:italic>\n -SMA), and inflammatory mediators (iNOS) were detected by Western blotting. IL-1\u03b2 and IL-6 mRNA levels were detected by quantitative real-time PCR. Human brain microvascular endothelial cells (HBMECs) were stimulated with\n P. gingivalis<\/jats:italic>\n -derived lipopolysaccharide (LPS) to mimic inflammation\n in vitro<\/jats:italic>\n . Endothelial-specific knockdown of USP22 in the hippocampus was achieved via adeno-associated virus (AAV) delivery to validate its role\n in vivo<\/jats:italic>\n . STRING bioinformatics tool to investigate its potential downstream pathways.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Oral infection with\n P. gingivalis<\/jats:italic>\n successfully induced periodontitis in mice and led to EndoMT in the hippocampus, characterized by downregulation of ZO-1 and Claudin-5 and upregulation of\n \u03b1<\/jats:italic>\n -SMA, along with inflammatory activation evidenced by elevated levels of iNOS, IL-1\u03b2 mRNA, and IL-6 mRNA. USP22 expression was significantly upregulated both in hippocampal tissues of\n P. gingivalis<\/jats:italic>\n -infected mice and in LPS-exposed HBMECs. Knockdown of USP22 attenuated LPS-induced EndoMT and suppressed the expression of inflammatory markers in HBMECs. Similarly, endothelial-specific knockdown of USP22 mitigated\n P. gingivalis<\/jats:italic>\n -induced EndoMT and hippocampal inflammation\n in vivo<\/jats:italic>\n .\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n These findings demonstrate that\n P. gingivalis<\/jats:italic>\n promotes EndoMT and neuroinflammation in the hippocampus. Endothelial-specific inhibition of USP22 alleviates BBB dysfunction and central inflammatory responses, highlighting USP22 as a potential therapeutic target for neuroinflammatory disorders associated with chronic periodontitis.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fnins.2026.1790970","type":"journal-article","created":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T06:47:43Z","timestamp":1773384463000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["USP22 knockdown attenuates P. gingivalis-induced EndoMT and CNS inflammation: a link between periodontitis and neuroinflammation"],"prefix":"10.3389","volume":"20","author":[{"given":"Hui","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Stomatology, Nantong First People\u2019s Hospital, Southeast University Affiliated Nantong First People\u2019s Hospital","place":["Nantong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mengxian","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Shanghai Geriatric Medical Center","place":["Shanghai, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiaming","family":"Shen","sequence":"additional","affiliation":[{"name":"Deparment of Pharmacy, Huai\u2019an Maternal and Child Health Hospital","place":["Huai\u2019an, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Intensive Care Unit, Nantong Hospital of Traditional Chinese Medicine, Nantong Hospital Affiliated to Nanjing University of Chinese Medicine","place":["Nantong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chengwei","family":"Duan","sequence":"additional","affiliation":[{"name":"Medical Research Center, Nantong First People\u2019s Hospital, Southeast University Affiliated Nantong First People\u2019s Hospital","place":["Nantong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,13]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"11831","DOI":"10.3390\/ijms222111831","article-title":"Periodontitis and gestational diabetes mellitus: a potential inflammatory vicious cycle","volume":"22","author":"Bendek","year":"2021","journal-title":"Int. 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