{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T16:40:09Z","timestamp":1768322409165,"version":"3.49.0"},"reference-count":75,"publisher":"MDPI AG","issue":"9","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":[{"name":"Science Technology Planning Project of Guangdong Province","award":["2019B010140002"],"award-info":[{"award-number":["2019B010140002"]}]},{"name":"Science Technology Planning Project of Guangdong Province","award":["2020B111110002"],"award-info":[{"award-number":["2020B111110002"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background and objective: Periodontitis, a chronic inflammatory disease driven by host immune dysregulation, leads to progressive destruction of periodontal tissues. This study employed an integrative approach combining single-cell transcriptomics, hierarchical weighted gene co-expression network analysis (hdWGCNA), and deep learning algorithms to identify key biomarkers associated with neutrophil degranulation in periodontitis, aiming to establish diagnostic models for early detection and precision interventions. Methods: We integrated single-cell RNA sequencing (scRNA-seq) data from human gingival tissues with bulk transcriptomic datasets. Pathogenic neutrophil subsets were characterized via pseudotime trajectory and cell\u2013cell communication analyses. Hierarchical weighted gene co-expression network analysis (hdWGCNA) identified functional modules linked to degranulation. Machine learning and a convolutional neural network (CNN) model combining gene expression and immune cell profiles were developed for diagnosis. Results: scRNA-seq revealed a neutrophil subpopulation significantly increased infiltration in periodontitis, with cell\u2013cell communication and pseudotime trajectory analyses demonstrating amplified inflammatory crosstalk. hdWGCNA identified the turquoise module enriched in PD-KEY-Neutrophils, containing hub genes linked to neutrophil degranulation and complement activation. Immune infiltration and non-negative matrix factorization linked high-degranulation neutrophil signatures to the periodontal immunity microenvironment. Machine learning demonstrated that the neutrophil degranulation-associated genes effectively distinguish diseased gingival tissue, suggesting their potential to predict periodontitis. Finally, integrating transcriptomic and immunological data, we developed a gene-immune CNN deep learning model accurately diagnosed periodontitis in diverse cohorts (AUC = 0.922). Conclusions: Our study identified a pathogenic neutrophil subpopulation driving periodontitis through degranulation and inflammation. The neutrophil degranulation genes serve as critical biomarkers, offering new insights for clinical diagnosis and treatment of periodontitis.<\/jats:p>","DOI":"10.3390\/genes16091005","type":"journal-article","created":{"date-parts":[[2025,8,26]],"date-time":"2025-08-26T10:35:17Z","timestamp":1756204517000},"page":"1005","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Diagnosis of Periodontitis via Neutrophil Degranulation Signatures Identified by Integrated scRNA-Seq and Deep Learning"],"prefix":"10.3390","volume":"16","author":[{"given":"Huijian","family":"Wu","sequence":"first","affiliation":[{"name":"School of Advanced Manufacturing, Guangdong University of Technology, Jieyang 522000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9636-499X","authenticated-orcid":false,"given":"Linqing","family":"Huang","sequence":"additional","affiliation":[{"name":"School of Advanced Manufacturing, Guangdong University of Technology, Jieyang 522000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuting","family":"Cai","sequence":"additional","affiliation":[{"name":"School of Integrated Circuits, Guangdong University of Technology, Guangzhou 510006, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2421-7621","authenticated-orcid":false,"given":"Xiaoming","family":"Xiong","sequence":"additional","affiliation":[{"name":"School of Integrated Circuits, Guangdong University of Technology, Guangzhou 510006, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"He","sequence":"additional","affiliation":[{"name":"School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17038","DOI":"10.1038\/nrdp.2017.38","article-title":"Periodontal diseases","volume":"3","author":"Kinane","year":"2017","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1177\/0022034514552491","article-title":"Global burden of severe periodontitis in 1990\u20132010: A systematic review and meta-regression","volume":"93","author":"Kassebaum","year":"2014","journal-title":"J. Dent. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1111\/prd.12344","article-title":"Clinical and public health implications of periodontal and systemic diseases: An overview","volume":"83","author":"Genco","year":"2020","journal-title":"Periodontol. 2000"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Isola, G., Giudice, A.L., Polizzi, A., Alibrandi, A., Patini, R., and Ferlito, S. (2019). Periodontitis and Tooth Loss Have Negative Systemic Impact on Circulating Progenitor Cell Levels: A Clinical Study. Genes, 10.","DOI":"10.3390\/genes10121022"},{"key":"ref_5","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_6","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1111\/prd.12430","article-title":"Interconnection of periodontal disease and comorbidities: Evidence, mechanisms, and implications","volume":"89","author":"Hajishengallis","year":"2022","journal-title":"Periodontol. 2000"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Zhou, M., Dong, J., Zha, L., and Liao, Y. (2021). Causal Association between Periodontal Diseases and Cardiovascular Diseases. Genes, 13.","DOI":"10.3390\/genes13010013"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Butera, A., Folini, E., Cosola, S., Russo, G., Scribante, A., Gallo, S., Stablum, G., Menchini Fabris, G.B., Covani, U., and Genovesi, A. (2023). Evaluation of the Efficacy of Probiotics Domiciliary Protocols for the Management of Periodontal Disease, in Adjunction of Non-Surgical Periodontal Therapy (NSPT): A Systematic Literature Review. Appl. Sci., 13.","DOI":"10.3390\/app13010663"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1111\/idj.12630","article-title":"Current Concepts in the Management of Periodontitis","volume":"71","author":"Kwon","year":"2021","journal-title":"Int. Dent. J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1111\/prd.12296","article-title":"The role of the microbiota in periodontal disease","volume":"83","author":"Curtis","year":"2020","journal-title":"Periodontol. 2000"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.it.2013.09.001","article-title":"Immunomicrobial pathogenesis of periodontitis: Keystones, pathobionts, and host response","volume":"35","author":"Hajishengallis","year":"2014","journal-title":"Trends Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Cavalla, F., Biguetti, C.C., Melchiades, J.L., Tabanez, A.P., Azevedo, M.C.S., Trombone, A.P.F., Faveri, M., Feres, M., and Garlet, G.P. (2018). Genetic Association with Subgingival Bacterial Colonization in Chronic Periodontitis. Genes, 9.","DOI":"10.3390\/genes9060271"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"111558","DOI":"10.1016\/j.intimp.2024.111558","article-title":"Association between periodontitis and inflammatory comorbidities: The common role of innate immune cells, underlying mechanisms and therapeutic targets","volume":"128","author":"Wu","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.1111\/odi.13884","article-title":"Innate and adaptive immunity of periodontal disease. From etiology to alveolar bone loss","volume":"28","year":"2022","journal-title":"Oral. Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1038\/s41368-024-00332-w","article-title":"The impact of aging on neutrophil functions and the contribution to periodontitis","volume":"17","author":"Wang","year":"2025","journal-title":"Int. J. Oral. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1902\/jop.2005.76.6.951","article-title":"Aberrant neutrophil reactions in periodontitis","volume":"76","author":"Figueredo","year":"2005","journal-title":"J. Periodontol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1111\/prd.12313","article-title":"New developments in neutrophil biology and periodontitis","volume":"82","author":"Hajishengallis","year":"2020","journal-title":"Periodontol. 2000"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Zhao, B., Fan, Q., Liu, J., Yin, A., Wang, P., and Zhang, W. (2022). Identification of Key Modules and Genes Associated with Major Depressive Disorder in Adolescents. Genes, 13.","DOI":"10.3390\/genes13030464"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1177\/0022034516645564","article-title":"Distinct Oral Neutrophil Subsets Define Health and Periodontal Disease States","volume":"95","author":"Fine","year":"2016","journal-title":"J. Dent. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1177\/00220345221145903","article-title":"Single-Cell Analyses of the Oral Mucosa Reveal Immune Cell Signatures","volume":"102","author":"Liu","year":"2023","journal-title":"J. Dent. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"100498","DOI":"10.1016\/j.crmeth.2023.100498","article-title":"hdWGCNA identifies co-expression networks in high-dimensional transcriptomics data","volume":"3","author":"Morabito","year":"2023","journal-title":"Cell Rep. Methods"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.7150\/thno.65694","article-title":"Single-cell RNA landscape of the osteoimmunology microenvironment in periodontitis","volume":"12","author":"Chen","year":"2022","journal-title":"Theranostics"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2112","DOI":"10.1902\/jop.2008.080139","article-title":"Transcriptomes in healthy and diseased gingival tissues","volume":"79","author":"Demmer","year":"2008","journal-title":"J. Periodontol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1177\/0022034514527288","article-title":"Gingival tissue transcriptomes identify distinct periodontitis phenotypes","volume":"93","author":"Kebschull","year":"2014","journal-title":"J. Dent. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1016\/j.cell.2019.05.031","article-title":"Comprehensive Integration of Single-Cell Data","volume":"177","author":"Stuart","year":"2019","journal-title":"Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1038\/s41467-021-21246-9","article-title":"Inference and analysis of cell-cell communication using CellChat","volume":"12","author":"Jin","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1038\/nbt.2859","article-title":"The dynamics and regulators of cell fate decisions are revealed by pseudotemporal ordering of single cells","volume":"32","author":"Trapnell","year":"2014","journal-title":"Nat. Biotechnol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: An R package for comparing biological themes among gene clusters","volume":"16","author":"Yu","year":"2012","journal-title":"Omics"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1038\/s41467-019-09234-6","article-title":"Metascape provides a biologist-oriented resource for the analysis of systems-level datasets","volume":"10","author":"Zhou","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v033.i01","article-title":"Regularization Paths for Generalized Linear Models via Coordinate Desc ent","volume":"33","author":"Friedman","year":"2010","journal-title":"J. Stat. Softw."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2789","DOI":"10.1093\/bioinformatics\/btab039","article-title":"mlr3proba: An R package for machine learning in survival analysis","volume":"37","author":"Sonabend","year":"2021","journal-title":"Bioinformatics"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Ramamurthy, E., Agarwal, S., Toong, N., Sestili, H., Kaplow, I.M., Chen, Z., Phan, B., and Pfenning, A.R. (2024). Regression convolutional neural network models implicate peripheral immune regulatory variants in the predisposition to Alzheimer\u2019s disease. PLoS Comput. Biol., 20.","DOI":"10.1371\/journal.pcbi.1012356"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Hung, J., Goodman, A., Ravel, D., Lopes, S.C.P., Rangel, G.W., Nery, O.A., Malleret, B., Nosten, F., Lacerda, M.V.G., and Ferreira, M.U. (2020). Keras R-CNN: Library for cell detection in biological images using deep neural networks. BMC Bioinform., 21.","DOI":"10.1186\/s12859-020-03635-x"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Novac, O.C., Chirodea, M.C., Novac, C.M., Bizon, N., Oproescu, M., Stan, O.P., and Gordan, C.E. (2022). Analysis of the Application Efficiency of TensorFlow and PyTorch in Convolutional Neural Network. Sensors, 22.","DOI":"10.3390\/s22228872"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Becht, E., Giraldo, N.A., Lacroix, L., Buttard, B., Elarouci, N., Petitprez, F., Selves, J., Laurent-Puig, P., Saut\u00e8s-Fridman, C., and Fridman, W.H. (2016). Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression. Genome Biol., 17.","DOI":"10.1186\/s13059-016-1070-5"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4164","DOI":"10.1073\/pnas.0308531101","article-title":"Metagenes and molecular pattern discovery using matrix factorization","volume":"101","author":"Brunet","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"111212","DOI":"10.1016\/j.cellsig.2024.111212","article-title":"CXCR4-mediated neutrophil dynamics in periodontitis","volume":"120","author":"Xu","year":"2024","journal-title":"Cell Signal"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1182\/blood-2006-04-017731","article-title":"Rho GTPase Rac1 is critical for neutrophil migration into the lung","volume":"109","author":"Filippi","year":"2007","journal-title":"Blood"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1111\/prd.12222","article-title":"The periodontal war: Microbes and immunity","volume":"75","author":"Ebersole","year":"2017","journal-title":"Periodontol. 2000"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1111\/imr.13152","article-title":"Neutrophils in the periodontium: Interactions with pathogens and roles in tissue homeostasis and inflammation","volume":"314","author":"Uriarte","year":"2023","journal-title":"Immunol. Rev."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Vitkov, L., Mu\u00f1oz, L.E., Schoen, J., Knopf, J., Schauer, C., Minnich, B., Herrmann, M., and Hannig, M. (2021). Neutrophils Orchestrate the Periodontal Pocket. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.788766"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Khan, M.A., Ali, Z.S., Sweezey, N., Grasemann, H., and Palaniyar, N. (2019). Progression of Cystic Fibrosis Lung Disease from Childhood to Adulthood: Neutrophils, Neutrophil Extracellular Trap (NET) Formation, and NET Degradation. Genes, 10.","DOI":"10.3390\/genes10030183"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.exphem.2020.10.001","article-title":"Periodontitis and circulating blood cell profiles: A systematic review and meta-analysis","volume":"93","author":"Botelho","year":"2021","journal-title":"Exp. Hematol."},{"key":"ref_45","first-page":"e36627","article-title":"Estimation and Co-Relation of the Neutrophil Count and Neutrophil Chemotaxis in Patients With Gingivitis, Chronic Periodontitis, and Localized Aggressive Periodontitis Compared With Healthy Controls","volume":"15","author":"Vanasi","year":"2023","journal-title":"Cureus"},{"key":"ref_46","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_47","doi-asserted-by":"crossref","unstructured":"Giordano, D., Kuley, R., Draves, K.E., Elkon, K.B., Giltiay, N.V., and Clark, E.A. (2023). B cell-activating factor (BAFF) from dendritic cells, monocytes and neutrophils is required for B cell maturation and autoantibody production in SLE-like autoimmune disease. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1050528"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"5686","DOI":"10.1158\/1078-0432.CCR-13-0405","article-title":"RG7212 anti-TWEAK mAb inhibits tumor growth through inhibition of tumor cell proliferation and survival signaling and by enhancing the host antitumor immune response","volume":"19","author":"Yin","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1450","DOI":"10.1002\/jbmr.3440","article-title":"Genomewide Association Study Identifies Cxcl Family Members as Partial Mediators of LPS-Induced Periodontitis","volume":"33","author":"Hiyari","year":"2018","journal-title":"J. Bone Miner. Res."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Sochalska, M., and Potempa, J. (2017). Manipulation of Neutrophils by Porphyromonas gingivalis in the Development of Periodontitis. Front. Cell Infect. Microbiol., 7.","DOI":"10.3389\/fcimb.2017.00197"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Makkawi, H., Hoch, S., Burns, E., Hosur, K., Hajishengallis, G., Kirschning, C.J., and Nussbaum, G. (2017). Porphyromonas gingivalis Stimulates TLR2-PI3K Signaling to Escape Immune Clearance and Induce Bone Resorption Independently of MyD88. Front. Cell Infect. Microbiol., 7.","DOI":"10.3389\/fcimb.2017.00359"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"111465","DOI":"10.1016\/j.intimp.2023.111465","article-title":"Blocking CXCR1\/2 attenuates experimental periodontitis by suppressing neutrophils recruitment","volume":"128","author":"Huang","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1177\/1753425915589387","article-title":"Peripheral blood neutrophil cytokine hyper-reactivity in chronic periodontitis","volume":"21","author":"Ling","year":"2015","journal-title":"Innate Immun."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Zimny, A., P\u0142onczy\u0144ska, A., Jakubowski, W., Zubrzycka, N., Potempa, J., and Sochalska, M. (2025). Porphyromonas gingivalis affects neutrophil pro-inflammatory activities. Front. Cell Dev. Biol., 13.","DOI":"10.3389\/fcell.2025.1419651"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1111\/prd.12342","article-title":"Periodontitis is an inflammatory disease of oxidative stress: We should treat it that way","volume":"84","author":"Sczepanik","year":"2020","journal-title":"Periodontol. 2000"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1111\/j.1600-0765.1995.tb01249.x","article-title":"Evidence of a direct relationship between neutrophil collagenase activity and periodontal tissue destruction in vivo: Role of active enzyme in human periodontitis","volume":"30","author":"Lee","year":"1995","journal-title":"J. Periodontal Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"e20221751","DOI":"10.1084\/jem.20221751","article-title":"Neutrophil extracellular traps and extracellular histones potentiate IL-17 inflammation in periodontitis","volume":"220","author":"Kim","year":"2023","journal-title":"J. Exp. Med."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Wang, J., Zhou, Y., Ren, B., Zou, L., He, B., and Li, M. (2021). The Role of Neutrophil Extracellular Traps in Periodontitis. Front. Cell Infect. Microbiol., 11.","DOI":"10.3389\/fcimb.2021.639144"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/j.jare.2024.07.028","article-title":"Single-cell atlas of human gingiva unveils a NETs-related neutrophil subpopulation regulating periodontal immunity","volume":"72","author":"Qiu","year":"2024","journal-title":"J. Adv. Res."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Sansores-Espa\u00f1a, L.D., Melgar-Rodr\u00edguez, S., Vernal, R., Carrillo-\u00c1vila, B.A., Mart\u00ednez-Aguilar, V.M., and D\u00edaz-Z\u00fa\u00f1iga, J. (2022). Neutrophil N1 and N2 Subsets and Their Possible Association with Periodontitis: A Scoping Review. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232012068"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1038\/nri3399","article-title":"Neutrophil recruitment and function in health and inflammation","volume":"13","author":"Kolaczkowska","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Nicu, E.A., Rijkschroeff, P., Wartewig, E., Nazmi, K., and Loos, B.G. (2018). Characterization of oral polymorphonuclear neutrophils in periodontitis patients: A case-control study. BMC Oral. Health, 18.","DOI":"10.1186\/s12903-018-0615-2"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1177\/00220345960750080601","article-title":"Human neutrophil gelatinase and associated lipocalin in adult and localized juvenile periodontitis","volume":"75","author":"Westerlund","year":"1996","journal-title":"J. Dent. Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1111\/paa.1999.111.5.383","article-title":"Myeloperoxidase","volume":"111","author":"Klebanoff","year":"1999","journal-title":"Proc. Assoc. Am. Physicians"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1111\/j.1600-0765.1998.tb02286.x","article-title":"Lactoferrin impedes epithelial cell adhesion in vitro","volume":"33","author":"Overman","year":"1998","journal-title":"J. Periodontal Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1111\/j.1600-0765.2006.00952.x","article-title":"Neutrophil elastase is involved in the initial destruction of human periodontal ligament","volume":"42","author":"Ujiie","year":"2007","journal-title":"J. Periodontal Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1002\/path.4423","article-title":"Macrophage-specific NOX2 contributes to the development of lung emphysema through modulation of SIRT1\/MMP-9 pathways","volume":"235","author":"Trocme","year":"2015","journal-title":"J. Pathol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1016\/j.celrep.2014.06.044","article-title":"A myeloperoxidase-containing complex regulates neutrophil elastase release and actin dynamics during NETosis","volume":"8","author":"Metzler","year":"2014","journal-title":"Cell Rep."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"3233","DOI":"10.4049\/jimmunol.170.6.3233","article-title":"Proinflammatory activities of S100: Proteins S100A8, S100A9, and S100A8\/A9 induce neutrophil chemotaxis and adhesion","volume":"170","author":"Ryckman","year":"2003","journal-title":"J. Immunol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"RP92895","DOI":"10.7554\/eLife.92895.3","article-title":"Genetic associations between circulating immune cells and periodontitis highlight the prospect of systemic immunoregulation in periodontal care","volume":"12","author":"Ye","year":"2024","journal-title":"Elife"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1370","DOI":"10.1016\/j.identj.2024.10.006","article-title":"Identification of Potential Biomarkers and Therapeutic Targets for Periodontitis","volume":"75","author":"Huoshen","year":"2025","journal-title":"Int. Dent. J."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Kim, H.D., Karna, S., Shin, Y., Vu, H., Cho, H.J., and Kim, S. (2021). S100A8 and S100A9 in saliva, blood and gingival crevicular fluid for screening established periodontitis: A cross-sectional study. BMC Oral. Health, 21.","DOI":"10.1186\/s12903-021-01749-z"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.1038\/s44318-024-00342-8","article-title":"A bipartite bacterial virulence factor targets the complement system and neutrophil activation","volume":"44","author":"Kurniyati","year":"2025","journal-title":"Embo J."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1799","DOI":"10.4103\/njcp.njcp_19_22","article-title":"The study of genetic predisposition on periodontitis and peri-implantitis","volume":"25","author":"Turkmen","year":"2022","journal-title":"Niger. J. Clin. Pract."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Yu, W., Hu, S., Yang, R., Lin, L., Mao, C., Jin, M., Gu, Y., Li, G., Jiang, B., and Gong, Y. (2022). Upregulated Vanins and their potential contribution to periodontitis. BMC Oral. Health, 22.","DOI":"10.1186\/s12903-022-02583-7"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/9\/1005\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:32:51Z","timestamp":1760034771000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/9\/1005"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,26]]},"references-count":75,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["genes16091005"],"URL":"https:\/\/doi.org\/10.3390\/genes16091005","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,26]]}}}