{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T23:06:37Z","timestamp":1791846397212,"version":"4.3.4"},"reference-count":33,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2024,12,10]],"date-time":"2024-12-10T00:00:00Z","timestamp":1733788800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"China Postdoctoral Science Foundation","award":["2024T171082"],"award-info":[{"award-number":["2024T171082"]}]},{"name":"China Postdoctoral Science Foundation","award":["2023M744003"],"award-info":[{"award-number":["2023M744003"]}]},{"name":"China Postdoctoral Science Foundation","award":["2023A1515110039"],"award-info":[{"award-number":["2023A1515110039"]}]},{"name":"Guangdong Basic and Applied Basic Research Foundation","award":["2024T171082"],"award-info":[{"award-number":["2024T171082"]}]},{"name":"Guangdong Basic and Applied Basic Research Foundation","award":["2023M744003"],"award-info":[{"award-number":["2023M744003"]}]},{"name":"Guangdong Basic and Applied Basic Research Foundation","award":["2023A1515110039"],"award-info":[{"award-number":["2023A1515110039"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mucosal immunity plays a critical role in the pathogenesis of inflammatory immune diseases. This study leverages single-cell RNA sequencing, spatial transcriptomics, and spatial proteomics to compare the cellular mechanisms involved in periodontitis between humans and mice, aiming to develop precise strategies to protect the gingival mucosal barrier. We identified key conserved and divergent features in cellular landscapes and transcriptional profiles across the two species, underscoring the complexity of inflammatory responses and immune dynamics in periodontitis. Additionally, we revealed a novel regulatory mechanism by which epithelial cells modulate macrophage behavior and inflammation through the JAG1\u2013Notch pathway. Validation through animal experiments revealed that JAG1 inhibition reduces inflammation in epithelial cells, mitigating periodontitis. Our findings advance the understanding of periodontal disease pathogenesis and highlight the importance of integrating human and animal model data to develop treatments aligned with human physiology, offering potential therapeutic targets for controlling inflammation and enhancing tissue regeneration.<\/jats:p>","DOI":"10.3390\/ijms252413255","type":"journal-article","created":{"date-parts":[[2024,12,10]],"date-time":"2024-12-10T08:40:10Z","timestamp":1733820010000},"page":"13255","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Single-Cell and Spatial Multi-Omics Analysis Reveal That Targeting JAG1 in Epithelial Cells Reduces Periodontal Inflammation and Alveolar Bone Loss"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8439-913X","authenticated-orcid":false,"given":"Shuhong","family":"Kuang","sequence":"first","affiliation":[{"name":"Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayu","family":"Yang","sequence":"additional","affiliation":[{"name":"Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zongshan","family":"Shen","sequence":"additional","affiliation":[{"name":"Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Xia","sequence":"additional","affiliation":[{"name":"Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1586-3741","authenticated-orcid":false,"given":"Zhengmei","family":"Lin","sequence":"additional","affiliation":[{"name":"Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1038\/s41577-020-00488-6","article-title":"Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities","volume":"21","author":"Hajishengallis","year":"2021","journal-title":"Nat. Rev. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4090","DOI":"10.1016\/j.cell.2021.05.013","article-title":"Human oral mucosa cell atlas reveals a stromal-neutrophil axis regulating tissue immunity","volume":"184","author":"Williams","year":"2021","journal-title":"Cell"},{"key":"ref_3","first-page":"Cd009376","article-title":"Supportive periodontal therapy (SPT) for maintaining the dentition in adults treated for periodontitis","volume":"2018","author":"Manresa","year":"2018","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_4","first-page":"100547","article-title":"Restoring periodontal tissue homoeostasis prevents cognitive decline by reducing the number of Serpina3n(high) astrocytes in the hippocampus","volume":"5","author":"Shen","year":"2024","journal-title":"Innovation"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"eaau4594","DOI":"10.1126\/sciimmunol.aau4594","article-title":"Regulation of host-microbe interactions at oral mucosal barriers by type 17 immunity","volume":"5","author":"Gaffen","year":"2020","journal-title":"Sci. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"eabl5450","DOI":"10.1126\/science.abl5450","article-title":"Fibrin is a critical regulator of neutrophil effector function at the oral mucosal barrier","volume":"374","author":"Silva","year":"2021","journal-title":"Science"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1007\/s11427-023-2467-1","article-title":"The spatial transcriptomic landscape of human gingiva in health and periodontitis","volume":"67","author":"Shen","year":"2023","journal-title":"Sci. China Life Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.archoralbio.2019.05.013","article-title":"Effects of Candida albicans infection on defense effector secretion by human oral mucosal epithelial cells","volume":"103","author":"Huang","year":"2019","journal-title":"Arch. Oral Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.immuni.2016.12.010","article-title":"On-going Mechanical Damage from Mastication Drives Homeostatic Th17 Cell Responses at the Oral Barrier","volume":"46","author":"Dutzan","year":"2017","journal-title":"Immunity"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Bai, L., Chen, B.-Y., Liu, Y., Zhang, W.-C., and Duan, S.-Z. (2022). A Mouse Periodontitis Model with Humanized Oral Bacterial Community. Front. Cell. Infect. Microbiol., 12.","DOI":"10.3389\/fcimb.2022.842845"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2247","DOI":"10.1038\/s41596-018-0035-4","article-title":"An experimental murine model to study periodontitis","volume":"13","author":"Marchesan","year":"2018","journal-title":"Nat. Protoc."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"8133","DOI":"10.1038\/s41467-023-43573-9","article-title":"Human and mouse neutrophils share core transcriptional programs in both homeostatic and inflamed contexts","volume":"14","author":"Hackert","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"17224","DOI":"10.1073\/pnas.1413624111","article-title":"Comparison of the transcriptional landscapes between human and mouse tissues","volume":"111","author":"Lin","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.jare.2023.02.017","article-title":"Single-cell sequencing reveals the evolution of immune molecules across multiple vertebrate species","volume":"55","author":"Jiao","year":"2024","journal-title":"J. Adv. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4012","DOI":"10.1038\/s41467-022-31659-9","article-title":"Spatially resolved proteomic map shows that extracellular matrix regulates epidermal growth","volume":"13","author":"Li","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1016\/j.immuni.2024.02.020","article-title":"Epithelial-derived interleukin-23 promotes oral mucosal immunopathology","volume":"57","author":"Kim","year":"2024","journal-title":"Immunity"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1111\/imm.12760","article-title":"The immune response to Prevotella bacteria in chronic inflammatory disease","volume":"151","author":"Larsen","year":"2017","journal-title":"Immunology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1016\/j.immuni.2023.01.002","article-title":"The landscape of immune dysregulation in Crohn\u2019s disease revealed through single-cell transcriptomic profiling in the ileum and colon","volume":"56","author":"Kong","year":"2023","journal-title":"Immunity"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1016\/j.cell.2020.12.016","article-title":"Spatiotemporal analysis of human intestinal development at single-cell resolution","volume":"184","author":"Antanaviciute","year":"2021","journal-title":"Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1111\/prd.12153","article-title":"The periodontal pocket: Pathogenesis, histopathology and consequences","volume":"76","author":"Bosshardt","year":"2018","journal-title":"Periodontology 2000"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1146\/annurev-immunol-070119-115104","article-title":"Interaction Between the Microbiota, Epithelia, and Immune Cells in the Intestine","volume":"38","author":"Kayama","year":"2020","journal-title":"Annu. Rev. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"eabo0924","DOI":"10.1126\/science.abo0924","article-title":"Connectomic comparison of mouse and human cortex","volume":"377","author":"Loomba","year":"2022","journal-title":"Science"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/j.devcel.2020.05.010","article-title":"Single-Cell RNA Sequencing of Human, Macaque, and Mouse Testes Uncovers Conserved and Divergent Features of Mammalian Spermatogenesis","volume":"54","author":"Shami","year":"2020","journal-title":"Dev. Cell"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.1161\/CIRCULATIONAHA.120.053361","article-title":"Nidogen-2 Maintains the Contractile Phenotype of Vascular Smooth Muscle Cells and Prevents Neointima Formation via Bridging Jagged1-Notch3 Signaling","volume":"144","author":"Mao","year":"2021","journal-title":"Circulation"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"eabe1692","DOI":"10.1126\/scitranslmed.abe1692","article-title":"Hepatocyte TLR4 triggers inter-hepatocyte Jagged1\/Notch signaling to determine NASH-induced fibrosis","volume":"13","author":"Yu","year":"2021","journal-title":"Sci. Transl. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e2350669","DOI":"10.1002\/eji.202350669","article-title":"Notch signaling in adipose tissue macrophages prevents diet-induced inflammation and metabolic dysregulation","volume":"54","author":"Siouti","year":"2024","journal-title":"Eur. J. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"L\u00f3pez-L\u00f3pez, S., de \u00c1vila, M.J.R., de Le\u00f3n, N.C.H., Ruiz-Marcos, F., Baladr\u00f3n, V., Nueda, M.L., Laborda, J., Garc\u00eda-Ram\u00edrez, J.J., Monsalve, E.M., and D\u00edaz-Guerra, M.J.M. (2021). NOTCH4 Exhibits Anti-Inflammatory Activity in Activated Macrophages by Interfering with Interferon-\u03b3 and TLR4 Signaling. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.734966"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Ayuthaya, B.I.N., Lertpimonchai, A., Samaranayake, L., Vathesatogkit, P., Thienpramuk, L., Wisitrasameewong, W., and Tamsailom, S. (2024). The Potential Effect of Periodontal Disease on the Development of Metabolic Syndrome: A 10-Year Observational Study in a Thai Adult Cohort. J. Clin. Periodontol.","DOI":"10.1111\/jcpe.14068"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1111\/prd.12379","article-title":"Association between metabolic syndrome and periodontitis: The role of lipids, inflammatory cytokines, altered host response, and the microbiome","volume":"87","author":"Pirih","year":"2021","journal-title":"Periodontology 2000"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Groeger, S., and Meyle, J. (2019). Oral Mucosal Epithelial Cells. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.00208"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/j.it.2017.08.005","article-title":"Tissue-Specific Immunity at the Oral Mucosal Barrier","volume":"39","author":"Moutsopoulos","year":"2018","journal-title":"Trends Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Rojas, C., Garc\u00eda, M.P., Polanco, A.F., Gonz\u00e1lez-Osuna, L., Sierra-Cristancho, A., Melgar-Rodr\u00edguez, S., Cafferata, E.A., and Vernal, R. (2021). Humanized Mouse Models for the Study of Periodontitis: An Opportunity to Elucidate Unresolved Aspects of Its Immunopathogenesis and Analyze New Immunotherapeutic Strategies. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.663328"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Lin, P., Niimi, H., Ohsugi, Y., Tsuchiya, Y., Shimohira, T., Komatsu, K., Liu, A., Shiba, T., Aoki, A., and Iwata, T. (2021). Application of Ligature-Induced Periodontitis in Mice to Explore the Molecular Mechanism of Periodontal Disease. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22168900"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/24\/13255\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:51:31Z","timestamp":1760115091000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/24\/13255"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,10]]},"references-count":33,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["ijms252413255"],"URL":"https:\/\/doi.org\/10.3390\/ijms252413255","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,10]]}}}