Lamont, R. J., Koo, H. & Hajishengallis, G. The oral microbiota: dynamic communities and host interactions. Nat. Rev. Microbiol. 16, 745–759 (2018).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Darveau, R. P. Periodontitis: a polymicrobial disruption of host homeostasis. Nat. Rev. Microbiol. 8, 481–490 (2010).

Article  CAS  PubMed  Google Scholar 

Maekawa, T. et al. Porphyromonas gingivalis manipulates complement and TLR signaling to uncouple bacterial clearance from inflammation and promote dysbiosis. Cell Host Microbe 15, 768–778 (2014).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Tsukasaki, M. et al. Host defense against oral microbiota by bone-damaging T cells. Nat. Commun. 9, 701 (2018).

Article  ADS  PubMed  PubMed Central  Google Scholar 

Tsukasaki, M. & Takayanagi, H. Osteoimmunology: evolving concepts in bone–immune interactions in health and disease. Nat. Rev. Immunol. 19, 626–642 (2019).

Article  CAS  PubMed  Google Scholar 

Hajishengallis, G. & Chavakis, T. Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities. Nat. Rev. Immunol. 21, 426–440 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Genco, R. J. & Sanz, M. Clinical and public health implications of periodontal and systemic diseases: An overview. Periodontol 2000 83, 7–13 (2020).

Article  PubMed  Google Scholar 

Xiao, E. et al. Diabetes Enhances IL-17 Expression and Alters the Oral Microbiome to Increase Its Pathogenicity. Cell Host Microbe 22, 120–128.e4 (2017).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Graves, D. T., Ding, Z. & Yang, Y. The impact of diabetes on periodontal diseases. Periodontol 2000 82, 214–224 (2020).

Article  PubMed  Google Scholar 

Mammen, M. J., Scannapieco, F. A. & Sethi, S. Oral-lung microbiome interactions in lung diseases. Periodontol 2000 83, 234–241 (2020).

Article  PubMed  Google Scholar 

Kitamoto, S. et al. The Intermucosal Connection between the Mouth and Gut in Commensal Pathobiont-Driven Colitis. Cell 182, 447–462.e14 (2020).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Caetano, A. J. et al. Defining human mesenchymal and epithelial heterogeneity in response to oral inflammatory disease. Elife 10, e62810 (2021).

Caetano, A. J., Human Cell Atlas Oral and Craniofacial Bionetwork, Sequeira, I. & Byrd, K. M. A Roadmap for the Human Oral and Craniofacial Cell Atlas. J. Dent. Res. 101, 1274–1288 (2022).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Caetano, A. J. et al. Spatially resolved transcriptomics reveals pro-inflammatory fibroblast involved in lymphocyte recruitment through CXCL8 and CXCL10. Elife 12, e81525 (2023).

Qian, S.-J. et al. Single-cell RNA sequencing identifies new inflammation-promoting cell subsets in Asian patients with chronic periodontitis. Front. Immunol. 12, 711337 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Williams, D. W. et al. Human oral mucosa cell atlas reveals a stromal-neutrophil axis regulating tissue immunity. Cell 184, 4090–4104.e15 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kondo, T., Gleason, A., Okawa, H., Hokugo, A. & Nishimura, I. Mouse gingival single-cell transcriptomic atlas: An activated fibroblast subpopulation guides oral barrier immunity in periodontitis. eLife https://doi.org/10.7554/elife.88183 (2023).

Kondo, T. et al. Oral microbial extracellular DNA initiates periodontitis through gingival degradation by fibroblast-derived cathepsin K in mice. Commun. Biol. 5, 962 (2022).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Abe, T. & Hajishengallis, G. Optimization of the ligature-induced periodontitis model in mice. J. Immunol. Methods 394, 49–54 (2013).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Dutzan, N. et al. A dysbiotic microbiome triggers TH17 cells to mediate oral mucosal immunopathology in mice and humans. Sci. Transl. Med. 10, eaat0797 (2018).

Udagawa, N. et al. Osteoclast differentiation by RANKL and OPG signaling pathways. J. Bone Miner. Metab. 39, 19–26 (2021).

Article  CAS  PubMed  Google Scholar 

Tsukasaki, M. RANKL and osteoimmunology in periodontitis. J. Bone Miner. Metab. 39, 82–90 (2021).

Article  CAS  PubMed  Google Scholar 

Kourtzelis, I. et al. DEL-1 promotes macrophage efferocytosis and clearance of inflammation. Nat. Immunol. 20, 40–49 (2019).

Article  CAS  PubMed  Google Scholar 

Men, Y. et al. Gli1+ periodontium stem cells are regulated by osteocytes and occlusal force. Dev. Cell 54, 639–654.e6 (2020).

Article  CAS  PubMed  Google Scholar 

Iwayama, T. et al. Plap-1 lineage tracing and single-cell transcriptomics reveal cellular dynamics in the periodontal ligament. Development 149, dev201203 (2022).

Jin, S. et al. Inference and analysis of cell-cell communication using CellChat. Nat. Commun. 12, 1088 (2021).

Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

Eskan, M. A. et al. The leukocyte integrin antagonist Del-1 inhibits IL-17-mediated inflammatory bone loss. Nat. Immunol. 13, 465–473 (2012).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Shin, J. et al. DEL-1 restrains osteoclastogenesis and inhibits inflammatory bone loss in nonhuman primates. Sci. Transl. Med. 7, 307ra155 (2015).

Article  PubMed  PubMed Central  Google Scholar 

Schmidt, E. P., Lee, W. L., Zemans, R. L., Yamashita, C. & Downey, G. P. On, around, and through: neutrophil-endothelial interactions in innate immunity. Physiology 26, 334–347 (2011).

Article  CAS  PubMed  Google Scholar 

Hajishengallis, G. New developments in neutrophil biology and periodontitis. Periodontol 2000 82, 78–92 (2020).

Article  PubMed  Google Scholar 

Walker, E. C. et al. Oncostatin M promotes bone formation independently of resorption when signaling through leukemia inhibitory factor receptor in mice. J. Clin. Invest. 120, 582–592 (2010).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Galli, C. et al. Targeted deletion of a distant transcriptional enhancer of the receptor activator of nuclear factor-kappaB ligand gene reduces bone remodeling and increases bone mass. Endocrinology 149, 146–153 (2008).

Article  ADS  CAS  PubMed  Google Scholar 

Onal, M. et al. Unique distal enhancers linked to the mouse Tnfsf11 gene direct tissue-specific and inflammation-induced expression of RANKL. Endocrinology 157, 482–496 (2016).

Article  CAS  PubMed  Google Scholar 

Bishop, K. A., Meyer, M. B. & Pike, J. W. A novel distal enhancer mediates cytokine induction of mouse RANKl gene expression. Mol. Endocrinol. 23, 2095–2110 (2009).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Onal, M. et al. The RANKL distal control region is required for the increase in RANKL expression, but not the bone loss, associated with hyperparathyroidism or lactation in adult mice. Mol. Endocrinol. 26, 341–348 (2012).

Article  CAS  PubMed  Google Scholar 

Silva, L. M., Kim, T. S. & Moutsopoulos, N. M. Neutrophils are gatekeepers of mucosal immunity. Immunol. Rev. 314, 125–141 (2023).

Article  CAS  PubMed  Google Scholar 

Dutzan, N., Konkel, J. E., Greenwell-Wild, T. & Moutsopoulos, N. M. Characterization of the human immune cell network at the gingival barrier. Mucosal Immunol. 9, 1163–1172 (2016).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Landzberg, M., Doering, H., Aboodi, G. M., Tenenbaum, H. C. & Glogauer, M. Quantifying oral inflammatory load: oral neutrophil counts in periodontal health and disease. J. Periodontal Res. 50, 330–336 (2015).

Article  CAS  PubMed  Google Scholar 

Silva, L. M. et al. Fibrin is a critical regulator of neutrophil effector function at the oral mucosal barrier. Science 374, eabl5450 (2021).

Article  CAS  PubMed  Google Scholar 

Kim, T. S. et al. Neutrophil extracellular traps and extracellular histones potentiate IL-17 inflammation in periodontitis. J. Exp. Med. 220, e20221751 (2023).

Assuma, R., Oates, T., Cochran, D., Amar, S. & Graves, D. T. IL-1 and TNF antagonists inhibit the inflammatory response and bone loss in experimental periodontitis. J. Immunol. 160, 403–409 (1998).

Article  CAS