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Chapple ILC, Hirschfeld J, Cockwell P, Dietrich T, Sharma P. Interplay between periodontitis and chronic kidney disease. Nat Rev Nephrol 2025; 21:226-240. [PMID: 39658571 DOI: 10.1038/s41581-024-00910-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/04/2024] [Indexed: 12/12/2024]
Abstract
Periodontitis is a ubiquitous chronic inflammatory disease affecting the supporting tissues of the teeth and is a major cause of multiple tooth loss. Despite being preventable, periodontitis and dental caries are responsible for more years lost to disability than any other human condition. The most severe form of periodontitis affects 1 billion individuals, and its prevalence is increasing globally. Periodontitis arises from a dysregulated and hyperactive inflammatory response to dysbiosis in the periodontal microbiome. This response has systemic effects associated with premature mortality and elevated risk of several systemic non-communicable diseases (NCDs), including atheromatous cardiovascular disease, type 2 diabetes and chronic kidney disease (CKD). This risk association between periodontitis and NCDs is independent of their shared common risk factors, suggesting that periodontitis is a non-traditional risk factor for NCDs such as CKD. As periodontitis progresses, the immune cells and mediators underpinning its pathophysiology leak into the systemic circulation through the ulcerated oral mucosal lining, inducing in a systemic inflammatory profile that closely mirrors that observed in patients with CKD. The relationship between periodontitis and CKD seems to be bi-directional, but large-scale intervention studies are required to clarify causality and could lead to new care pathways for managing each condition as an exposure for the other.
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Affiliation(s)
- Iain L C Chapple
- Periodontal Research Group, Institute of Clinical Sciences, University of Birmingham and Birmingham Community Healthcare NHS Foundation Trust, Birmingham, UK.
- NIHR Birmingham Biomedical Research Centre in Inflammation, Birmingham, UK.
| | - Josefine Hirschfeld
- Periodontal Research Group, Institute of Clinical Sciences, University of Birmingham and Birmingham Community Healthcare NHS Foundation Trust, Birmingham, UK
- NIHR Birmingham Biomedical Research Centre in Inflammation, Birmingham, UK
| | - Paul Cockwell
- Department of Nephrology, University Hospital Birmingham, Birmingham, UK
| | - Thomas Dietrich
- Periodontal Research Group, Institute of Clinical Sciences, University of Birmingham and Birmingham Community Healthcare NHS Foundation Trust, Birmingham, UK
- NIHR Birmingham Biomedical Research Centre in Inflammation, Birmingham, UK
| | - Praveen Sharma
- Periodontal Research Group, Institute of Clinical Sciences, University of Birmingham and Birmingham Community Healthcare NHS Foundation Trust, Birmingham, UK
- NIHR Birmingham Biomedical Research Centre in Inflammation, Birmingham, UK
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2
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Zhang G, Zheng J, Zhou Y, Zhou M, Zhang J, Liu Y, Geng Y, Wang W, Xin M, Yang B, Zhang L, Huang L. From teeth to bone: dental caries has causal effects on osteoporosis and osteoporotic fracture. BMC Oral Health 2025; 25:340. [PMID: 40045256 PMCID: PMC11881354 DOI: 10.1186/s12903-025-05735-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Accepted: 02/28/2025] [Indexed: 03/09/2025] Open
Abstract
OBJECTIVES Evidence from observational studies suggested oral diseases (periodontitis (PD) and dental caries) may increase susceptibility to bone loss. However, inherent confounding of observational studies limits causal interpretation. We aimed to conduct Mendelian randomization (MR) analysis to estimate the causal effect of oral diseases on osteoporosis (OP), bone mineral density (BMD) and fracture risk. METHODS We used summary-level GWAS meta-analysis data from the GLIDE consortium to identify 7 and 17 single-nucleotide polymorphisms (SNPs) for periodontitis and DMFS (the sum of Decayed, Missing, and Filled tooth Surfaces) as the instrumental variables. MR analyses of these instruments were performed on European individuals for the association with BMD of forearm, femoral neck and lumbar spine; and individuals from FinnGen consortium for OP, OP with pathological fracture, postmenopausal OP with pathological fracture, and site-specific fractures. We performed single-variable Mendelian randomization (SVMR) and multivariable Mendelian randomization (MVMR) to simultaneously assess independent causal effects of PD and DMFS on different outcomes. The estimates were primarily derived using inverse variance weighted (IVW) methods. Sensitivity analyses included weighted median, MR-egger, and Leave-one-out test. RESULTS In MVMR, after adjusting for PD, DMFS has a positive causal effect osteoporosis (OR = 1.165, [95% CI 1.020 to 1.331, P = 0.025]) and postmenopausal OP with pathological fracture (OR = 1.422, [95% CI 1.027 to 1.969, P = 0.034]). However, these causal relationships were not observed in the single-variable Mendelian randomization (SVMR) analysis. The causal associations were robust in various sensitivity analyses. CONCLUSIONS In conclusion, dental caries causally increases the risk of OP and postmenopausal OP with pathological fracture, suggesting the existence of teeth-bone axis. Proactive osteoporosis screening in patients with severe dental caries may be warranted for clinical consideration.
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Affiliation(s)
- Gongzi Zhang
- Department of Rehabilitation, Chinese PLA General Hospital, No.28 Fuxing Road, Haidian District, Beijing, 100853, People's Republic of China
- Department of Orthopedics, Chinese PLA General Hospital, No.28 Fuxing Road, Haidian District, Beijing, 100853, People's Republic of China
| | - Juan Zheng
- Department of Rehabilitation, Chinese PLA General Hospital, No.28 Fuxing Road, Haidian District, Beijing, 100853, People's Republic of China
| | - Ying Zhou
- Department of Rehabilitation, Chinese PLA General Hospital, No.28 Fuxing Road, Haidian District, Beijing, 100853, People's Republic of China
| | - Ming Zhou
- Department of Rehabilitation, Chinese PLA General Hospital, No.28 Fuxing Road, Haidian District, Beijing, 100853, People's Republic of China
| | - Jiali Zhang
- Department of Rehabilitation, Chinese PLA General Hospital, No.28 Fuxing Road, Haidian District, Beijing, 100853, People's Republic of China
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing, China
| | - Yangxiaoxue Liu
- Department of Rehabilitation, Chinese PLA General Hospital, No.28 Fuxing Road, Haidian District, Beijing, 100853, People's Republic of China
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing, China
| | - Yuhan Geng
- Department of Rehabilitation, Chinese PLA General Hospital, No.28 Fuxing Road, Haidian District, Beijing, 100853, People's Republic of China
| | - Wenxin Wang
- Department of Rehabilitation, Chinese PLA General Hospital, No.28 Fuxing Road, Haidian District, Beijing, 100853, People's Republic of China
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing, China
| | - Min Xin
- Department of Rehabilitation, Chinese PLA General Hospital, No.28 Fuxing Road, Haidian District, Beijing, 100853, People's Republic of China
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing, China
| | - Bo Yang
- Department of Graduate School, Tianjin Medical University, Tianjin, China
| | - Lihai Zhang
- Department of Orthopedics, Chinese PLA General Hospital, No.28 Fuxing Road, Haidian District, Beijing, 100853, People's Republic of China.
| | - Liping Huang
- Department of Rehabilitation, Chinese PLA General Hospital, No.28 Fuxing Road, Haidian District, Beijing, 100853, People's Republic of China.
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Schaefer AS, Nibali L, Zoheir N, Moutsopoulos NM, Loos BG. Genetic risk variants implicate impaired maintenance and repair of periodontal tissues as causal for periodontitis-A synthesis of recent findings. Periodontol 2000 2025. [PMID: 39953674 DOI: 10.1111/prd.12622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 12/18/2024] [Accepted: 12/29/2024] [Indexed: 02/17/2025]
Abstract
Periodontitis is a complex inflammatory disease in which the host genome, in conjunction with extrinsic factors, determines susceptibility and progression. Genetic predisposition is the strongest risk factor in the first decades of life. As people age, chronic exposure to the periodontal microbiome puts a strain on the proper maintenance of barrier function. This review summarizes our current knowledge on genetic risk factors implicated in periodontitis, derived (i) from hypothesis-free systematic whole genome-profiling studies (genome-wide association studies [GWAS] and quantitative trait loci [QTL] mapping studies), and independently validated through further unbiased approaches; (ii) from monogenic and oligogenic forms of periodontitis; and (iii) from syndromic forms of periodontitis. The genes include, but are not limited to, SIGLEC5, PLG, ROBO2, ABCA1, PF4, and CTSC. Notably, CTSC and PLG gene mutations were also identified in non-syndromic and syndromic forms of prepubertal and early-onset periodontitis. The functions of the identified genes in this review suggest that the pathways affected by the periodontitis-associated gene variants converge in functions involved in the maintenance and repair of structural integrity of the periodontal tissues. Particularly, these genes play a role in the healing of inflamed and ulcerated periodontal tissues, including roles in fibrinolysis, extrusion of cellular debris, extracellular matrix remodeling and angiogenesis. Syndromes that include periodontitis in their phenotype indicate that neutrophils play an important role in the regulation of inflammation in the periodontium. The established genetic susceptibility genes therefore collectively provide new insights into the molecular mechanisms and plausible causal factors underlying periodontitis.
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Affiliation(s)
- Arne S Schaefer
- Department of Periodontology, Oral Medicine and Oral Surgery, Institute for Dental and Craniofacial Sciences, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Luigi Nibali
- Periodontology Unit, Faculty of Dentistry, Oral and Craniofacial Sciences, Centre for Host Microbiome Interactions, King's College London, London, UK
| | - Noha Zoheir
- Periodontology Unit, Faculty of Dentistry, Oral and Craniofacial Sciences, Centre for Host Microbiome Interactions, King's College London, London, UK
| | - Niki M Moutsopoulos
- Oral Immunity and Infection Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA
| | - Bruno G Loos
- Department of Periodontology, Academic Center for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
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Cui Z, Wang P, Gao W. Microbial dysbiosis in periodontitis and peri-implantitis: pathogenesis, immune responses, and therapeutic. Front Cell Infect Microbiol 2025; 15:1517154. [PMID: 40007610 PMCID: PMC11850578 DOI: 10.3389/fcimb.2025.1517154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Accepted: 01/22/2025] [Indexed: 02/27/2025] Open
Abstract
The oral microbiome comprises over 700 distinct species, forming complex biofilms essential for maintaining oral and systemic health. When the microbial homeostasis in the periodontium is disrupted, pathogens within the biofilm can cause periodontitis and peri-implantitis, inducing host immune responses. Understanding the role of microbial communities and the immune mechanisms in oral health and disease is crucial for developing improved preventive, diagnostic and therapeutic strategies. However, many questions remain about how changes in bacterial populations contribute to the development and progression of these conditions. An electronic and manual literature search was conducted using PubMed, Excerpta Medica, Frontiers Reports and the Wiley Online Library databases for relevant articles. Data from these publications were extracted and the overall findings were summarized in a narrative manner. The variations in microbial communities and immune responses of periodontitis and peri-implantitis are explored. Dysbiosis of the subgingival microbiome-characterized by an increase in pathogenic bacteria such as Porphyromonas gingivalis, Tannerella forsythia, and Aggregatibacter actinomycetemcomitans-plays a pivotal role in the initiation and progression of periodontitis. As for peri-implantitis, alterations include a higher abundance of opportunistic pathogens and reduced microbial diversity around implants. Moreover, oral dysbiosis potentially influencing systemic health through immune-mediated pathways. Regional immunity of periodontium involving neutrophils, T helper cells-17, and immune-related cytokines is crucial for maintaining periodontal homeostasis and responding to microbial imbalances. Additionally, the impact of non-mechanical treatments-such as probiotics and laser therapy-on the oral microbiome is discussed, demonstrating their potential in managing microbial dysbiosis. These findings underscore that bacterial dysbiosis is a central factor in the development of periodontitis and peri-implantitis. Maintaining microbial balance is essential for preventing these diseases, and interventions targeting the microbiome could enhance treatment outcomes. Strategies focusing on controlling pathogenic bacteria, modulating immune responses, and promoting tissue regeneration are key to restoring periodontal stability. Further research is needed to clarify the mechanisms underlying the transition from peri-implant mucositis to peri-implantitis and to optimize prevention and treatment approaches, considering the complex interactions between the microbiome and host immunity.
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Affiliation(s)
| | | | - Weiyue Gao
- Stomatology Center, Gansu Provincial Hospital, Lanzhou, Gansu, China
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Hajishengallis G, Netea MG, Chavakis T. Trained immunity in chronic inflammatory diseases and cancer. Nat Rev Immunol 2025:10.1038/s41577-025-01132-x. [PMID: 39891000 DOI: 10.1038/s41577-025-01132-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/06/2025] [Indexed: 02/03/2025]
Abstract
A decade after the term 'trained immunity' (TRIM) was coined to reflect the long-lasting hyper-responsiveness of innate immune cells with an epigenetically imprinted 'memory' of earlier stimuli, our understanding has broadened to include the potential implications of TRIM in health and disease. Here, after summarizing the well-documented beneficial effects of TRIM against infections, we discuss emerging evidence that TRIM is also a major underlying mechanism in chronic inflammation-related disorders such as periodontitis, rheumatoid arthritis and cardiovascular disease. Furthermore, mounting evidence indicates that the induction of TRIM by certain agonists confers protective antitumour responses. Although the mechanisms underlying TRIM require further study, the current knowledge enables the experimental development of innovative therapeutic approaches to stimulate or inhibit TRIM in a context-appropriate manner, such as the stimulation of TRIM in cancer or its inhibition in inflammatory disorders.
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Affiliation(s)
- George Hajishengallis
- Department of Basic and Translational Sciences, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.
| | - Mihai G Netea
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.
- Department of Immunology and Metabolism, LIMES, University of Bonn, Bonn, Germany.
| | - Triantafyllos Chavakis
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
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Zimny A, Płonczyńska A, Jakubowski W, Zubrzycka N, Potempa J, Sochalska M. Porphyromonas gingivalis affects neutrophil pro-inflammatory activities. Front Cell Dev Biol 2025; 13:1419651. [PMID: 39936030 PMCID: PMC11811088 DOI: 10.3389/fcell.2025.1419651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Accepted: 01/13/2025] [Indexed: 02/13/2025] Open
Abstract
Porphyromonas gingivalis is the primary pathogen responsible for the development of periodontal inflammatory disease. Although gingipains are the major virulence factor of the pathogen, their role in impairing apoptosis and immune cell function is not fully understood. To investigate the impact of gingipains on neutrophil viability and function, we conducted studies using murine HoxB8 neutrophils and primary human neutrophils infected with wild-type strains of Porphyromonas gingivalis (W83 and ATCC 33277), or a gingipains-null mutant with deleted gingipains encoding genes, or wild-type bacteria preincubated with specific gingipain inhibitors. Flow cytometry revealed that wild-type Porphyromonas gingivalis had a marked effect on neutrophil viability regulated by anti-apoptotic proteins belonging to the Bcl-2 family; however, these effects were independent of gingipain expression or activity. Importantly, experiments using primary human neutrophils and macrophages revealed that gingipains play a significant role in the disruption of immune cell functions via the induction of reactive oxygen species and inactivation of neutrophil elastase activity. Additionally, although gingipains played a role in modulating the IL-8-dependent inflammatory response of human neutrophils, they did not affect the expression levels of pro-inflammatory cytokines TNF-α and IL-6.
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Affiliation(s)
- Agnieszka Zimny
- Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
| | - Alicja Płonczyńska
- Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
- Doctoral School of Exact and Natural Sciences, Jagiellonian University, Krakow, Poland
| | - Wiktor Jakubowski
- Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
| | - Natalia Zubrzycka
- Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
- Doctoral School of Exact and Natural Sciences, Jagiellonian University, Krakow, Poland
| | - Jan Potempa
- Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
- Department of Oral Immunity and Infectious Diseases, University of Louisville School of Dentistry, Louisville, KY, United States
| | - Maja Sochalska
- Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
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Ghasemi S, Mortezagholi B, Movahed E, Ghaedi A, Bazrgar A, Abdolalizadehil S, Khanzadeh S. Systematic review and meta-analysis of the association of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio with periodontitis. Eur J Med Res 2024; 29:581. [PMID: 39696713 DOI: 10.1186/s40001-024-02175-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 11/25/2024] [Indexed: 12/20/2024] Open
Abstract
INTRODUCTION Recent evidence suggests the relationship between periodontitis and systemic inflammation, which complete blood count can assess (CBC)-derived biomarkers such as neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR). We conducted this meta-analysis to evaluate the levels of NLR and PLR of patients with periodontitis compared to those of healthy controls. METHODS: Web of Science, PubMed, ProQuest, Scopus, and Open Grey were searched for studies published before October 20, 2024, without any limitation on date and language; then, using the random-effects model, we reported a standardized mean difference (SMD) with a 95% confidence interval (CI). In order to assess the quality of publications, we used the Newcastle-Ottawa scale (NOS). Our study was registered in PROSPERO (CRD42023475214). RESULTS Overall, 11 articles were included in the analysis. We found that patients with periodontitis had elevated levels of NLR compared to healthy controls (SMD = 0.30, 95% CI 0.08-0.52, p = 0.007) In the subgroup analysis according to race, patients with periodontitis had elevated levels of NLR compared to healthy controls in among East Asian patients (SMD = 0.35, 95% CI 0.15-0.55, p = 0.001), but not among Turkish (SMD = 0.15, 95% CI - 0.30-0.61, p = 0.50) and Indian (SMD = 0.38, 95% CI - 0.17-0.94, p = 0.18) patients. In addition, PLR level was not different among patients with periodontitis and healthy controls (SMD = 0.06, 95% CI - 0.71-0.83, p = 0.87). CONCLUSIONS The findings of our investigation, which indicate higher NLR levels in periodontitis patients, show that immune dysregulation plays a role in the etiology of the disease.
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Affiliation(s)
- Saeideh Ghasemi
- Dental School, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Bardia Mortezagholi
- Dental Research Center, Faculty of Dentistry, Islamic Azad University of Medical Sciences, Tehran, Iran
| | - Emad Movahed
- Dental Research Center, Faculty of Dentistry, Islamic Azad University of Medical Sciences, Tehran, Iran
| | - Arshin Ghaedi
- Student Research Committee, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Aida Bazrgar
- Student Research Committee, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Samira Abdolalizadehil
- Department of Epidemiology and Biostatistics, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
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Irwandi RA, Marruganti C, Collins G, Carvalho JDS, Gilroy D, D’Aiuto F. The translational potential of inflammation-induced skin blister human models in exploring the pathogenesis of periodontitis and its systemic health implications. Front Immunol 2024; 15:1469828. [PMID: 39737182 PMCID: PMC11682961 DOI: 10.3389/fimmu.2024.1469828] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 12/02/2024] [Indexed: 01/01/2025] Open
Abstract
Periodontitis is a highly prevalent chronic disease. Despite decades of extensive research on the topic, a complete understanding of its immunopathogenesis, especially when linked to other inflammatory comorbidities, is lacking. Ex vivo human and in vivo animal experiments have shown the host inflammatory response's crucial role in both the disease's onset and its systemic implications. These approaches, however, remain questionable when translating these findings into real-world scenarios linked to periodontitis. A clear need for new in vivo human models is discussed, especially within the context of understanding the host response to key pathogens linked to periodontitis, such as Porphyromonas gingivalis (P. gingivalis). Therefore, a skin blister model was employed to describe the stages of the host immune response in humans after challenges by microbial and/or sterile insults. A novel human challenge model using UV-killed P. gingivalis holds promise in producing new evidence and bridging the gap of the host response to periodontitis and its links with other common chronic diseases.
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Affiliation(s)
- Rizky Aditya Irwandi
- Periodontology Unit, UCL Eastman Dental Institute, University College London, London, United Kingdom
- Department of Oral Biology, Faculty of Dentistry, Universitas Indonesia, Jakarta, Indonesia
| | - Crystal Marruganti
- Periodontology Unit, UCL Eastman Dental Institute, University College London, London, United Kingdom
- Unit of Periodontology, Endodontology and Restorative Dentistry, Department of Medical Biotechnologies, University of Siena, Siena, Italy
| | - George Collins
- Department of Ageing, Rheumatology and Regenerative Medicine, Division of Medicine, University College London, London, United Kingdom
- Department of Cardiology, St Bartholomew’s Hospital, Barts Health NHS Trust, London, United Kingdom
| | - Jhonatan de Souza Carvalho
- Department of Ageing, Rheumatology and Regenerative Medicine, Division of Medicine, University College London, London, United Kingdom
- Department of Diagnosis and Surgery, São Paulo State University (UNESP), School of Dentistry, Araraquara, Brazil
| | - Derek Gilroy
- Department of Ageing, Rheumatology and Regenerative Medicine, Division of Medicine, University College London, London, United Kingdom
| | - Francesco D’Aiuto
- Periodontology Unit, UCL Eastman Dental Institute, University College London, London, United Kingdom
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Schulze-Späte U, Wurschi L, van der Vorst EPC, Hölzle F, Craveiro RB, Wolf M, Noels H. Crosstalk between periodontitis and cardiovascular risk. Front Immunol 2024; 15:1469077. [PMID: 39717783 PMCID: PMC11663742 DOI: 10.3389/fimmu.2024.1469077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 11/06/2024] [Indexed: 12/25/2024] Open
Abstract
Recent demographic developments resulted in an aged society with a rising disease burden of systemic and non-communicable diseases (NCDs). In cardiovascular disease (CVD), a NCD with high morbidity and mortality, recent preventive strategies include the investigation of comorbidities to reduce its significant economic burden. Periodontal disease, an oral bacterial-induced inflammatory disease of tooth-supporting tissue, is regulated in its prevalence and severity by the individual host response to a dysbiotic oral microbiota. Clinically, both NCDs are highly associated; however, shared risk factors such as smoking, obesity, type II diabetes mellitus and chronic stress represent only an insufficient explanation for the multifaceted interactions of both disease entities. Specifically, the crosstalk between both diseases is not yet fully understood. This review summarizes current knowledge on the clinical association of periodontitis and CVD, and elaborates on how periodontitis-induced pathophysiological mechanisms in patients may contribute to increased cardiovascular risk with focus on atherosclerosis. Clinical implications as well as current and future therapy considerations are discussed. Overall, this review supports novel scientific endeavors aiming at improving the quality of life with a comprehensive and integrated approach to improve well-being of the aging populations worldwide.
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Affiliation(s)
- Ulrike Schulze-Späte
- Section of Geriodontics, Department of Conservative Dentistry and Periodontics, University Hospital Jena, Jena, Germany
| | - Ludwig Wurschi
- Section of Geriodontics, Department of Conservative Dentistry and Periodontics, University Hospital Jena, Jena, Germany
| | - Emiel P. C. van der Vorst
- Institute for Molecular Cardiovascular Research (IMCAR), Uniklinik RWTH Aachen, RWTH Aachen University, Aachen, Germany
- Aachen-Maastricht Institute for Cardiorenal Research (AMICARE), Uniklinik RWTH Aachen, RWTH Aachen University, Aachen, Germany
- Interdisciplinary Center for Clinical Research (IZKF), RWTH Aachen University, Aachen, Germany
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich, Munich, Germany
| | - Frank Hölzle
- Department of Oral and Maxillofacial Surgery, School of Medicine, Uniklinik RWTH Aachen, Aachen, Germany
| | - Rogerio B. Craveiro
- Department of Orthodontics, Dental Clinic, Uniklinik RWTH Aachen, Aachen, Germany
| | - Michael Wolf
- Department of Orthodontics, Dental Clinic, Uniklinik RWTH Aachen, Aachen, Germany
| | - Heidi Noels
- Institute for Molecular Cardiovascular Research (IMCAR), Uniklinik RWTH Aachen, RWTH Aachen University, Aachen, Germany
- Aachen-Maastricht Institute for Cardiorenal Research (AMICARE), Uniklinik RWTH Aachen, RWTH Aachen University, Aachen, Germany
- Biochemistry Department, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, Netherlands
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Wang Q, Lin W, Lei K, Wang H, Zhang X, Jiang S, Zhang D, Wang W, Cao S, Li Y, Yu B, Wang Y, Yin Q, Yuan Q. Hyperglycemia-Enhanced Neutrophil Extracellular Traps Drive Mucosal Immunopathology at the Oral Barrier. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2407346. [PMID: 39499780 DOI: 10.1002/advs.202407346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 10/15/2024] [Indexed: 11/07/2024]
Abstract
Type 2 diabetes (T2D) is a risk factor for mucosal homeostasis and enhances the susceptibility to inflammation, in which neutrophils have been increasingly appreciated for their role. Here, barrier disruption and inflammation are observed at oral mucosa (gingiva) of T2D patients and mice. It is demonstrated that neutrophils infiltrate the gingival mucosa of T2D mice and expel obvious neutrophil extracellular traps (NETs), while removal of NETs alleviates the disruption of mucosal barrier. Mechanistically, gingival neutrophils released NETs are dependent of their metabolic reprogramming. Under hyperglycemic condition, neutrophils elevate both glucose incorporation and glycolysis via increased expression of GLUT1. Moreover, significantly increased levels of NETs are observed in local gingival lesions of patients, which are associated with clinical disease severity. This work elucidates a causative link between hyperglycemia and oral mucosal immunopathology, mediated by the altered immuno-metabolic axis in neutrophil, thereby suggesting a potential therapeutic strategy.
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Affiliation(s)
- Qian Wang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China
- Department of Prosthodontics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Weimin Lin
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Kexin Lei
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Hui Wang
- Department of Basic and Translational Sciences, Laboratory of Innate Immunity and Inflammation, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Xiaohan Zhang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Shuang Jiang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Danting Zhang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Wen Wang
- Hebei Key Laboratory of Stomatology, Hebei Clinical Research Center for Oral Diseases, Hebei Medical University, Shijiazhuang, Hebei, 050017, China
| | - Shuqin Cao
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Yuyu Li
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Bo Yu
- Division of Preventive and Restorative Sciences, School of Dentistry, University of California Los Angeles, Los Angeles, CA, 90095, USA
| | - Yuan Wang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Qi Yin
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Quan Yuan
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China
- Department of Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China
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11
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Li X, Chen X, Zhu Q, Zhang P, Nan S, Lv L, Qi S. D-mannose alleviates chronic periodontitis in rats by regulating the functions of neutrophils. BMC Oral Health 2024; 24:1336. [PMID: 39487474 PMCID: PMC11529006 DOI: 10.1186/s12903-024-05080-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Accepted: 10/17/2024] [Indexed: 11/04/2024] Open
Abstract
BACKGROUND Periodontitis is a chronic inflammatory disease characterized by the destruction of the components of the periodontium. It significantly impacts oral health and has been linked to systemic conditions like cardiovascular disease and diabetes. The critical role of neutrophils in the occurrence and development of chronic periodontitis has been paid increasing attention. The study aimed to explore the protective effects of D-mannose on chronic periodontitis and determine whether its underlying mechanisms is related to neutrophils. METHODS To explore the protective effects of D-mannose on chronic periodontitis, the eight-week-old Sprague Dawley rat model of lipopolysaccharide (LPS)-induced periodontitis was established, followed by D-mannose treatment by oral gavage. To evaluate the protective effects of D-mannose against periodontal bone loss, methylene blue staining, hematoxylin and eosin (H&E) staining, and micro-CT scanning were utilized. Then, immunofluorescence (IF), Western Blot, and RT-PCR were applied to assess the expression levels of pro-inflammatory cytokines (IL-1β, IL-6, and IL-17), anti-inflammatory cytokine (IL-10), tumor necrosis factor-alpha (TNF-α), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), ten-eleven translocation 2 (TET2), and key glycolytic enzymes (HK1, HK2, PFKFB3), and to examine D-mannose's impact on the recruitment and activation of neutrophils in the gingiva. Additionally, neutrophils isolated from the peripheral blood of healthy rats were treated with LPS and D-mannose, and changes in the expression levels of myeloperoxidase (MPO), IL-1β, IL-6, IL-17, IL-10, and TET2 were observed via IF. RESULTS In vivo, D-mannose inhibited LPS-induced alveolar bone resorption in rats. After D-mannose treatment, the expression levels of IL-17 (p<0.01) and TET2 (p<0.01) were suppressed by IF, and the expression levels of IL-1β (p<0.05), IL-17 (p<0.05) and TET2 (p<0.01) were downregulated by WB. The results of qPCR showed that D-mannose reduced the expression levels of IL-1β (p<0.05), IL-6 (p<0.01), IL-17 (p<0.01), TNF-α (p<0.01), G-CSF (p<0.01), GM-CSF (p<0.01), TET2 (p<0.01), HK1 (p<0.01), HK2 (p<0.01), and PFKFB3 (p<0.01). D-mannose also inhibited the recruitment and activation of neutrophils in LPS-treated rat gingival tissues. In vitro, the results of IF showed that D-mannose inhibited the activation of neutrophils stimulated by LPS, downregulated the expression of IL-1β (p < 0.05), IL-6, IL-17 (p < 0.01), and TET2 (p < 0.01), and upregulated the expression of IL-10 (p < 0.01). CONCLUSIONS D-mannose can alleviate chronic periodontitis in rats by regulating the functions of neutrophils, potentially associated with the expression of TET2 and glycolysis, providing new insights into the potential application of D-mannose to chronic periodontitis.
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Affiliation(s)
- Xue Li
- Department of Prothodontics, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases, Fudan University, Shanghai, China
| | - Xueting Chen
- Department of Prothodontics, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases, Fudan University, Shanghai, China
| | - Qingyu Zhu
- Department of Prothodontics, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases, Fudan University, Shanghai, China
| | - Pengye Zhang
- Department of Prothodontics, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases, Fudan University, Shanghai, China
| | - Shunxue Nan
- Department of Prothodontics, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases, Fudan University, Shanghai, China
| | - Lei Lv
- Ministry of Education Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
| | - Shengcai Qi
- Department of Prothodontics, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, China.
- Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases, Fudan University, Shanghai, China.
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12
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Muchova M, Kuehne SA, Grant MM, Smith PP, Nagi M, Chapple ILC, Hirschfeld J. Fusobacterium nucleatum elicits subspecies-specific responses in human neutrophils. Front Cell Infect Microbiol 2024; 14:1449539. [PMID: 39450334 PMCID: PMC11499235 DOI: 10.3389/fcimb.2024.1449539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2024] [Accepted: 09/06/2024] [Indexed: 10/26/2024] Open
Abstract
Fusobacterium nucleatum as a Gram-negative anaerobe plays a key bridging role in oral biofilms. It is involved in periodontal and extraoral diseases, the most prominent being colorectal cancer. Five subspecies are recognised: animalis, fusiforme, nucleatum, polymorphum and vincentii. Subspecies interact with neutrophils constantly patrolling tissues to remove microbial intruders. Neutrophil antimicrobial activities include generation of reactive oxygen species (ROS), formation of neutrophil extracellular traps (NETs) and release of cytokines and neutrophil enzymes. Subspecies-specific differences in immunogenicity have previously been observed in a neutrophil-like cell line but were not investigated in human neutrophils. Additionally, neutrophil responses to planktonic and biofilm-grown F. nucleatum have not been studied to date. The aims of this study were to compare the immunogenicity of planktonic and biofilm-grown F. nucleatum and to investigate potential differences in human neutrophil responses when stimulated with individual F. nucleatum subspecies. Human neutrophils isolated from peripheral blood were stimulated with planktonic and biofilm-grown F. nucleatum subspecies. Generation of ROS and NET formation were quantified by luminescence and fluorescence assays, respectively. Secretion of cytokines (IL-1β, TNF-α, IL-6, IL-8), neutrophil elastase and matrix metalloproteinase-9 was quantified by enzyme-linked immunosorbent assay (ELISA). Neutrophil responses showed biofilm-grown bacteria induced a significantly higher total and intracellular ROS response, as well as shorter time to total ROS release. Biofilm-grown F. nucleatum led to significantly lower IL-1β release. We found significant differences among individual subspecies in terms of total, intracellular ROS and extracellular superoxide. Subspecies polymorphum stimulated the highest mean amount of NET release. Amounts of cytokines released differed significantly among subspecies, while no differences were found in lysosomal enzyme release. Immunogenicity of F. nucleatum in human neutrophils is highly subspecies-specific in vitro with regard to ROS release and cytokine production. Understanding subspecies-specific immunogenicity of F. nucleatum may facilitate the discovery of novel therapeutic targets in F. nucleatum-mediated diseases.
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Affiliation(s)
- Maria Muchova
- Periodontal Research Group, Birmingham School of Dentistry, Institute of Clinical Sciences, The University of Birmingham, Birmingham, United Kingdom
| | - Sarah A. Kuehne
- School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom
| | - Melissa M. Grant
- Periodontal Research Group, Birmingham School of Dentistry, Institute of Clinical Sciences, The University of Birmingham, Birmingham, United Kingdom
- Birmingham Dental Hospital, Birmingham Community Health National Health Service (NHS) Foundation Trust, Birmingham, United Kingdom
- Birmingham National Institute for Health and Care Research (NIHR) Biomedical Research Centre (BRC) in Inflammation, Birmingham University, Birmingham, United Kingdom
| | - Peter P. Smith
- Periodontal Research Group, Birmingham School of Dentistry, Institute of Clinical Sciences, The University of Birmingham, Birmingham, United Kingdom
| | - Malee Nagi
- Periodontal Research Group, Birmingham School of Dentistry, Institute of Clinical Sciences, The University of Birmingham, Birmingham, United Kingdom
| | - Iain L. C. Chapple
- Periodontal Research Group, Birmingham School of Dentistry, Institute of Clinical Sciences, The University of Birmingham, Birmingham, United Kingdom
- Birmingham Dental Hospital, Birmingham Community Health National Health Service (NHS) Foundation Trust, Birmingham, United Kingdom
- Birmingham National Institute for Health and Care Research (NIHR) Biomedical Research Centre (BRC) in Inflammation, Birmingham University, Birmingham, United Kingdom
| | - Josefine Hirschfeld
- Periodontal Research Group, Birmingham School of Dentistry, Institute of Clinical Sciences, The University of Birmingham, Birmingham, United Kingdom
- Birmingham Dental Hospital, Birmingham Community Health National Health Service (NHS) Foundation Trust, Birmingham, United Kingdom
- Birmingham National Institute for Health and Care Research (NIHR) Biomedical Research Centre (BRC) in Inflammation, Birmingham University, Birmingham, United Kingdom
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13
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Konkel JE, Cox JR, Wemyss K. Bite-sized immunology; damage and microbes educating immunity at the gingiva. Mucosal Immunol 2024; 17:1141-1150. [PMID: 39038755 DOI: 10.1016/j.mucimm.2024.07.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 07/09/2024] [Accepted: 07/16/2024] [Indexed: 07/24/2024]
Abstract
Immune cells residing at the gingiva experience diverse and unique signals, tailoring their functions to enable them to appropriately respond to immunological challenges and maintain tissue integrity. The gingiva, defined as the mucosal barrier that surrounds and supports the teeth, is the only barrier site completely transected by a hard structure, the tooth. The tissue is damaged in early life during tooth eruption and chronically throughout life by the process of mastication. This occurs alongside challenges typical of barrier sites, including exposure to invading pathogens, the local commensal microbial community and environmental antigens. This review will focus on the immune network safeguarding gingival integrity, which is far less understood than that resident at other barrier sites. A detailed understanding of the gingiva-resident immune network is vital as it is the site of the inflammatory disease periodontitis, the most common chronic inflammatory condition in humans which has well-known detrimental systemic effects. Furthering our understanding of how the immune populations within the gingiva develop, are tailored in health, and how this is dysregulated in disease would further the development of effective therapies for periodontitis.
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Affiliation(s)
- Joanne E Konkel
- Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK.
| | - Joshua R Cox
- Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK
| | - Kelly Wemyss
- Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK
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14
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Boșca AB, Dinte E, Mihu CM, Pârvu AE, Melincovici CS, Șovrea AS, Mărginean M, Constantin AM, Băbțan AM, Muntean A, Ilea A. Local Drug Delivery Systems as Novel Approach for Controlling NETosis in Periodontitis. Pharmaceutics 2024; 16:1175. [PMID: 39339210 PMCID: PMC11435281 DOI: 10.3390/pharmaceutics16091175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 09/02/2024] [Accepted: 09/04/2024] [Indexed: 09/30/2024] Open
Abstract
Periodontitis is a chronic inflammation caused by periodontopathogenic bacteria in the dental biofilm, and also involves the inflammatory-immune response of the host. Polymorphonuclear neutrophils (PMNs) play essential roles in bacterial clearance by multiple mechanisms, including the formation of neutrophil extracellular traps (NETs) that retain and destroy pathogens. During PD progression, the interaction between PMNs, NETs, and bacteria leads to an exaggerated immune response and a prolonged inflammatory state. As a lesion matures, PMNs accumulate in the periodontal tissues and die via NETosis, ultimately resulting in tissue injury. A better understanding of the role of NETs, the associated molecules, and the pathogenic pathways of NET formation in periodontitis, could provide markers of NETosis as reliable diagnostic and prognostic tools. Moreover, an assessment of NET biomarker levels in biofluids, particularly in saliva or gingival crevicular fluid, could be useful for monitoring periodontitis progression and treatment efficacy. Preventing excessive NET accumulation in periodontal tissues, by both controlling NETs' formation and their appropriate removal, could be a key for further development of more efficient therapeutic approaches. In periodontal therapy, local drug delivery (LDD) systems are more targeted, enhancing the bioavailability of active pharmacological agents in the periodontal pocket and surrounding tissues for prolonged time to ensure an optimal therapeutic outcome.
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Affiliation(s)
- Adina Bianca Boșca
- Department of Histology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (A.B.B.)
| | - Elena Dinte
- Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Carmen Mihaela Mihu
- Department of Histology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (A.B.B.)
| | - Alina Elena Pârvu
- Department of Pathophysiology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Carmen Stanca Melincovici
- Department of Histology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (A.B.B.)
| | - Alina Simona Șovrea
- Department of Histology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (A.B.B.)
| | - Mariana Mărginean
- Department of Histology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (A.B.B.)
| | - Anne-Marie Constantin
- Department of Histology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (A.B.B.)
| | - Anida-Maria Băbțan
- Department of Oral Rehabilitation, Faculty of Dentistry, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania (A.I.)
| | - Alexandrina Muntean
- Department of Paediatric Dentistry, Faculty of Dentistry, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Aranka Ilea
- Department of Oral Rehabilitation, Faculty of Dentistry, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania (A.I.)
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15
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Wu Q, Zhang W, Lu Y, Li H, Yang Y, Geng F, Liu J, Lin L, Pan Y, Li C. Association between periodontitis and inflammatory comorbidities: The common role of innate immune cells, underlying mechanisms and therapeutic targets. Int Immunopharmacol 2024; 128:111558. [PMID: 38266446 DOI: 10.1016/j.intimp.2024.111558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Revised: 01/11/2024] [Accepted: 01/15/2024] [Indexed: 01/26/2024]
Abstract
Periodontitis, which is related to various systemic diseases, is a chronic inflammatory disease caused by periodontal dysbiosis of the microbiota. Multiple factors can influence the interaction of periodontitis and associated inflammatory disorders, among which host immunity is an important contributor to this interaction. Innate immunity can be activated aberrantly because of the systemic inflammation induced by periodontitis. This aberrant activation not only exacerbates periodontal tissue damage but also impairs systemic health, triggering or aggravating inflammatory comorbidities. Therefore, innate immunity is a potential therapeutic target for periodontitis and associated inflammatory comorbidities. This review delineates analogous aberrations of innate immune cells in periodontitis and comorbid conditions such as atherosclerosis, diabetes, obesity, and rheumatoid arthritis. The mechanisms behind these changes in innate immune cells are discussed, including trained immunity and clonal hematopoiesis of indeterminate potential (CHIP), which can mediate the abnormal activation and myeloid-biased differentiation of hematopoietic stem and progenitor cells. Besides, the expansion of myeloid-derived suppressor cells (MDSCs), which have immunosuppressive and osteolytic effects on peripheral tissues, also contributes to the interaction between periodontitis and its inflammatory comorbidities. The potential treatment targets for relieving the risk of both periodontitis and systemic conditions are also elucidated, such as the modulation of innate immunity cells and mediators, the regulation of trained immunity and CHIP, as well as the inhibition of MDSCs' expansion.
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Affiliation(s)
- Qibing Wu
- Department of Periodontology, School and Hospital of Stomatology, China Medical University, Shenyang, China; Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Weijia Zhang
- Department of Periodontology, School and Hospital of Stomatology, China Medical University, Shenyang, China
| | - Yaqiong Lu
- Department of Periodontology, School and Hospital of Stomatology, China Medical University, Shenyang, China; Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Hongxia Li
- Department of Periodontology, School and Hospital of Stomatology, China Medical University, Shenyang, China; Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Yaru Yang
- Department of Periodontology, School and Hospital of Stomatology, China Medical University, Shenyang, China
| | - Fengxue Geng
- Department of Periodontology, School and Hospital of Stomatology, China Medical University, Shenyang, China; Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Jinwen Liu
- Department of Periodontology, School and Hospital of Stomatology, China Medical University, Shenyang, China; Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Li Lin
- Department of Periodontology, School and Hospital of Stomatology, China Medical University, Shenyang, China
| | - Yaping Pan
- Department of Periodontology, School and Hospital of Stomatology, China Medical University, Shenyang, China
| | - Chen Li
- Department of Periodontology, School and Hospital of Stomatology, China Medical University, Shenyang, China; Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China.
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16
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Poser M, Sing KEA, Ebert T, Ziebolz D, Schmalz G. The rosetta stone of successful ageing: does oral health have a role? Biogerontology 2023; 24:867-888. [PMID: 37421489 PMCID: PMC10615965 DOI: 10.1007/s10522-023-10047-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 06/19/2023] [Indexed: 07/10/2023]
Abstract
Ageing is an inevitable aspect of life and thus successful ageing is an important focus of recent scientific efforts. The biological process of ageing is mediated through the interaction of genes with environmental factors, increasing the body's susceptibility to insults. Elucidating this process will increase our ability to prevent and treat age-related disease and consequently extend life expectancy. Notably, centenarians offer a unique perspective on the phenomenon of ageing. Current research highlights several age-associated alterations on the genetic, epigenetic and proteomic level. Consequently, nutrient sensing and mitochondrial function are altered, resulting in inflammation and exhaustion of regenerative ability.Oral health, an important contributor to overall health, remains underexplored in the context of extreme longevity. Good masticatory function ensures sufficient nutrient uptake, reducing morbidity and mortality in old age. The relationship between periodontal disease and systemic inflammatory pathologies is well established. Diabetes, rheumatoid arthritis and cardiovascular disease are among the most significant disease burdens influenced by inflammatory oral health conditions. Evidence suggests that the interaction is bi-directional, impacting progression, severity and mortality. Current models of ageing and longevity neglect an important factor in overall health and well-being, a gap that this review intends to illustrate and inspire avenues for future research.
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Affiliation(s)
- Maximilian Poser
- Department of Cariology, Endodontology and Periodontology, University Leipzig, Liebigstr. 12, 04103, Leipzig, Germany.
| | - Katie E A Sing
- Department of Medicine, Royal Devon and Exeter Hospital, University of Exeter Medical School, Exeter, EX2 5DW, UK
| | - Thomas Ebert
- Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig, Liebigstr. 20, 04103, Leipzig, Germany
| | - Dirk Ziebolz
- Department of Cariology, Endodontology and Periodontology, University Leipzig, Liebigstr. 12, 04103, Leipzig, Germany
| | - Gerhard Schmalz
- Department of Cariology, Endodontology and Periodontology, University Leipzig, Liebigstr. 12, 04103, Leipzig, Germany
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17
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Kim K, Su Y, Kucine AJ, Cheng K, Zhu D. Guided Bone Regeneration Using Barrier Membrane in Dental Applications. ACS Biomater Sci Eng 2023; 9:5457-5478. [PMID: 37650638 DOI: 10.1021/acsbiomaterials.3c00690] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/01/2023]
Abstract
Guided bone regeneration (GBR) is a widely used technique in preclinical and clinical studies due to its predictability. Its main purpose is to prevent the migration of soft tissue into the osseous wound space, while allowing osseous cells to migrate to the site. GBR is classified into two main categories: resorbable and non-resorbable membranes. Resorbable membranes do not require a second surgery but tend to have a short resorption period. Conversely, non-resorbable membranes maintain their mechanical strength and prevent collapse. However, they require removal and are susceptible to membrane exposure. GBR is often used with bone substitute graft materials to fill the defect space and protect the bone graft. The membrane can also undergo various modifications, such as surface modification and biological factor loading, to improve barrier functions and bone regeneration. In addition, bone regeneration is largely related to osteoimmunology, a new field that focuses on the interactions between bone and the immune system. Understanding these interactions can help in developing new treatments for bone diseases and injuries. Overall, GBR has the potential to be a powerful tool in promoting bone regeneration. Further research in this area could lead to advancements in the field of bone healing. This review will highlight resorbable and non-resorbable membranes with cellular responses during bone regeneration, provide insights into immunological response during bone remodeling, and discuss antibacterial features.
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Affiliation(s)
- Kakyung Kim
- Department of Biomedical Engineering, Stony Brook University, Stony Brook, New York 11794, United States
| | - Yingchao Su
- Department of Biomedical Engineering, Stony Brook University, Stony Brook, New York 11794, United States
| | - Allan J Kucine
- Department of Oral and Maxillofacial Surgery, Stony Brook University, Stony Brook, New York 11794, United States
| | - Ke Cheng
- Department of Biomedical Engineering, Columbia University, New York City, New York 10027, United States
| | - Donghui Zhu
- Department of Biomedical Engineering, Stony Brook University, Stony Brook, New York 11794, United States
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18
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Li Y, Chen Y, Cai G, Ni Q, Geng Y, Wang T, Bao C, Ruan X, Wang H, Sun W. Roles of trained immunity in the pathogenesis of periodontitis. J Periodontal Res 2023; 58:864-873. [PMID: 37424315 DOI: 10.1111/jre.13158] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 06/16/2023] [Accepted: 06/28/2023] [Indexed: 07/11/2023]
Abstract
Periodontitis is a chronic, inflammatory, and destructive disease caused by the imbalance of host immune response and dental biofilm, and has strong epidemiological and pathogenesis correlations with systemic diseases. The immune response in periodontitis involves both innate and adaptive immunity, with numerous immune cells and inflammatory pathways participating in a complex network of interactions. In the past decade, the concept of "trained immunity" has emerged, which highlights the memory characteristics of innate immunity, thus opening up a new avenue of research. There is growing interest in exploring the role of trained immunity in chronic inflammatory and metabolic diseases such as atherosclerosis and diabetes mellitus. Evidence suggests that trained immunity may also regulate the onset and progression of periodontitis, serving as a bridge between periodontitis-related comorbidities. In this review, we summarize concepts related to trained immunity and its development. Furthermore, we present current evidence that endorses the notion of trained immunity in periodontitis and analyze possible roles it may assume regarding periodontitis-associated inflammatory reactions from a cellular perspective. Finally, we discuss various clinical therapeutic strategies for periodontitis and its associated comorbidities that target trained immunity. We hope that more researchers will pay attention to this emerging concept, thereby providing deeper insights into this novel field.
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Affiliation(s)
- Yingyi Li
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
- Department of Orthodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Yue Chen
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Guanhui Cai
- Department of Orthodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Qiaoqi Ni
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Ying Geng
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Ting Wang
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
- Department of Orthodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Chen Bao
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Xiaolei Ruan
- Department of Orthodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Hua Wang
- Department of Orthodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Wen Sun
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
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Su Y, Ye L, Hu C, Zhang Y, Liu J, Shao L. Periodontitis as a promoting factor of T2D: current evidence and mechanisms. Int J Oral Sci 2023; 15:25. [PMID: 37321994 PMCID: PMC10272210 DOI: 10.1038/s41368-023-00227-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Revised: 04/12/2023] [Accepted: 04/26/2023] [Indexed: 06/17/2023] Open
Abstract
Periodontitis is an infectious disease caused by an imbalance between the local microbiota and host immune response. Epidemiologically, periodontitis is closely related to the occurrence, development, and poor prognosis of T2D and is recognized as a potential risk factor for T2D. In recent years, increasing attention has been given to the role of the virulence factors produced by disorders of the subgingival microbiota in the pathological mechanism of T2D, including islet β-cell dysfunction and insulin resistance (IR). However, the related mechanisms have not been well summarized. This review highlights periodontitis-derived virulence factors, reviews how these stimuli directly or indirectly regulate islet β-cell dysfunction. The mechanisms by which IR is induced in insulin-targeting tissues (the liver, visceral adipose tissue, and skeletal muscle) are explained, clarifying the influence of periodontitis on the occurrence and development of T2D. In addition, the positive effects of periodontal therapy on T2D are overviewed. Finally, the limitations and prospects of the current research are discussed. In summary, periodontitis is worthy of attention as a promoting factor of T2D. Understanding on the effect of disseminated periodontitis-derived virulence factors on the T2D-related tissues and cells may provide new treatment options for reducing the risk of T2D associated with periodontitis.
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Affiliation(s)
- Yuan Su
- Stomatology Center, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, China
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Leilei Ye
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Chen Hu
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yanli Zhang
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Jia Liu
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Longquan Shao
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China.
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20
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Hascoët E, Blanchard F, Blin-Wakkach C, Guicheux J, Lesclous P, Cloitre A. New insights into inflammatory osteoclast precursors as therapeutic targets for rheumatoid arthritis and periodontitis. Bone Res 2023; 11:26. [PMID: 37217496 DOI: 10.1038/s41413-023-00257-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 03/02/2023] [Accepted: 03/09/2023] [Indexed: 05/24/2023] Open
Abstract
Rheumatoid arthritis (RA) and periodontitis are chronic inflammatory diseases leading to increased bone resorption. Preventing this inflammatory bone resorption is a major health challenge. Both diseases share immunopathogenic similarities and a common inflammatory environment. The autoimmune response or periodontal infection stimulates certain immune actors, leading in both cases to chronic inflammation that perpetuates bone resorption. Moreover, RA and periodontitis have a strong epidemiological association that could be explained by periodontal microbial dysbiosis. This dysbiosis is believed to be involved in the initiation of RA via three mechanisms. (i) The dissemination of periodontal pathogens triggers systemic inflammation. (ii) Periodontal pathogens can induce the generation of citrullinated neoepitopes, leading to the generation of anti-citrullinated peptide autoantibodies. (iii) Intracellular danger-associated molecular patterns accelerate local and systemic inflammation. Therefore, periodontal dysbiosis could promote or sustain bone resorption in distant inflamed joints. Interestingly, in inflammatory conditions, the existence of osteoclasts distinct from "classical osteoclasts" has recently been reported. They have proinflammatory origins and functions. Several populations of osteoclast precursors have been described in RA, such as classical monocytes, a dendritic cell subtype, and arthritis-associated osteoclastogenic macrophages. The aim of this review is to synthesize knowledge on osteoclasts and their precursors in inflammatory conditions, especially in RA and periodontitis. Special attention will be given to recent data related to RA that could be of potential value in periodontitis due to the immunopathogenic similarities between the two diseases. Improving our understanding of these pathogenic mechanisms should lead to the identification of new therapeutic targets involved in the pathological inflammatory bone resorption associated with these diseases.
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Affiliation(s)
- Emilie Hascoët
- Nantes Université, Oniris, Univ Angers, CHU Nantes, INSERM, Regenerative Medicine and Skeleton, RMeS, UMR 1229, F-44000, Nantes, France
| | - Frédéric Blanchard
- Nantes Université, Oniris, Univ Angers, CHU Nantes, INSERM, Regenerative Medicine and Skeleton, RMeS, UMR 1229, F-44000, Nantes, France
| | | | - Jérôme Guicheux
- Nantes Université, Oniris, Univ Angers, CHU Nantes, INSERM, Regenerative Medicine and Skeleton, RMeS, UMR 1229, F-44000, Nantes, France.
| | - Philippe Lesclous
- Nantes Université, Oniris, Univ Angers, CHU Nantes, INSERM, Regenerative Medicine and Skeleton, RMeS, UMR 1229, F-44000, Nantes, France
| | - Alexandra Cloitre
- Nantes Université, Oniris, Univ Angers, CHU Nantes, INSERM, Regenerative Medicine and Skeleton, RMeS, UMR 1229, F-44000, Nantes, France
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21
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Hajishengallis G. Illuminating the oral microbiome and its host interactions: animal models of disease. FEMS Microbiol Rev 2023; 47:fuad018. [PMID: 37113021 PMCID: PMC10198557 DOI: 10.1093/femsre/fuad018] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Revised: 04/24/2023] [Accepted: 04/26/2023] [Indexed: 04/29/2023] Open
Abstract
Periodontitis and caries are driven by complex interactions between the oral microbiome and host factors, i.e. inflammation and dietary sugars, respectively. Animal models have been instrumental in our mechanistic understanding of these oral diseases, although no single model can faithfully reproduce all aspects of a given human disease. This review discusses evidence that the utility of an animal model lies in its capacity to address a specific hypothesis and, therefore, different aspects of a disease can be investigated using distinct and complementary models. As in vitro systems cannot replicate the complexity of in vivo host-microbe interactions and human research is typically correlative, model organisms-their limitations notwithstanding-remain essential in proving causality, identifying therapeutic targets, and evaluating the safety and efficacy of novel treatments. To achieve broader and deeper insights into oral disease pathogenesis, animal model-derived findings can be synthesized with data from in vitro and clinical research. In the absence of better mechanistic alternatives, dismissal of animal models on fidelity issues would impede further progress to understand and treat oral disease.
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Affiliation(s)
- George Hajishengallis
- Department of Basic and Translational Sciences, Laboratory of Innate Immunity and Inflammation, School of Dental Medicine, University of Pennsylvania, 240 S. 40th Street, Philadelphia, PA 19104-6030, USA
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22
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Abdulkareem AA, Al-Taweel FB, Al-Sharqi AJ, Gul SS, Sha A, Chapple IL. Current concepts in the pathogenesis of periodontitis: from symbiosis to dysbiosis. J Oral Microbiol 2023; 15:2197779. [PMID: 37025387 PMCID: PMC10071981 DOI: 10.1080/20002297.2023.2197779] [Citation(s) in RCA: 104] [Impact Index Per Article: 52.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Accepted: 03/28/2023] [Indexed: 04/05/2023] Open
Abstract
The primary etiological agent for the initiation and progression of periodontal disease is the dental plaque biofilm which is an organized aggregation of microorganisms residing within a complex intercellular matrix. The non-specific plaque hypothesis was the first attempt to explain the role of the dental biofilm in the pathogenesis of periodontal diseases. However, the introduction of sophisticated diagnostic and laboratory assays has led to the realisation that the development of periodontitis requires more than a mere increase in the biomass of dental plaque. Indeed, multispecies biofilms exhibit complex interactions between the bacteria and the host. In addition, not all resident microorganisms within the biofilm are pathogenic, since beneficial bacteria exist that serve to maintain a symbiotic relationship between the plaque microbiome and the host's immune-inflammatory response, preventing the emergence of pathogenic microorganisms and the development of dysbiosis. This review aims to highlight the development and structure of the dental plaque biofilm and to explore current literature on the transition from a healthy (symbiotic) to a diseased (dysbiotic) biofilm in periodontitis and the associated immune-inflammatory responses that drive periodontal tissue destruction and form mechanistic pathways that impact other systemic non-communicable diseases.
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Affiliation(s)
- Ali A. Abdulkareem
- Department of Periodontics, College of Dentistry, University of Baghdad, Baghdad, Iraq
| | - Firas B. Al-Taweel
- Department of Periodontics, College of Dentistry, University of Baghdad, Baghdad, Iraq
| | - Ali J.B. Al-Sharqi
- Department of Periodontics, College of Dentistry, University of Baghdad, Baghdad, Iraq
| | - Sarhang S. Gul
- College of Dentistry, University of Sulaimani, Sulaimani, Iraq
| | - Aram Sha
- College of Dentistry, University of Sulaimani, Sulaimani, Iraq
| | - Iain L.C. Chapple
- Periodontal Research Group, Institute of Clinical Sciences, College of Medical & Dental Sciences, University of Birmingham, Birmingham, UK
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23
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Xu T, Xie K, Wang C, Ivanovski S, Zhou Y. Immunomodulatory nanotherapeutic approaches for periodontal tissue regeneration. NANOSCALE 2023; 15:5992-6008. [PMID: 36896757 DOI: 10.1039/d2nr06149j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/18/2023]
Abstract
Periodontitis is an infection-induced inflammatory disease characterized by progressive destruction of tooth supporting tissues, which, if left untreated, can result in tooth loss. The destruction of periodontal tissues is primarily caused by an imbalance between the host immune protection and immune destruction mechanisms. The ultimate goal of periodontal therapy is to eliminate inflammation and promote the repair and regeneration of both hard and soft tissues, so as to restore the physiological structure and function of periodontium. Advancement in nanotechnologies has enabled the development of nanomaterials with immunomodulatory properties for regenerative dentistry. This review discusses the immune mechanisms of the major effector cells in the innate and adaptive immune systems, the physicochemical and biological properties of nanomaterials, and the research advancements in immunomodulatory nanotherapeutic approaches for the management of periodontitis and the regeneration of periodontal tissues. The current challenges, and prospects for future applications of nanomaterials are then discussed so that researchers at the intersections of osteoimmunology, regenerative dentistry and materiobiology will continue to advance the development of nanomaterials for improved periodontal tissue regeneration.
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Affiliation(s)
- Tian Xu
- School of Dentistry, The University of Queensland, QLD 4006, Australia.
| | - Kunke Xie
- Clinical Laboratory, Bo'Ai Hospital of Zhongshan, 6 Chenggui Road, East District, Zhongshan 528403, Guangdong, China
| | - Cong Wang
- School of Dentistry, The University of Queensland, QLD 4006, Australia.
| | - Sašo Ivanovski
- School of Dentistry, The University of Queensland, QLD 4006, Australia.
| | - Yinghong Zhou
- School of Dentistry, The University of Queensland, QLD 4006, Australia.
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24
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Abstract
Mucosal tissues are constantly exposed to the outside environment. They receive signals from the commensal microbiome and tissue-specific triggers including alimentary and airborne elements and are tasked to maintain balance in the absence of inflammation and infection. Here, we present neutrophils as sentinel cells in mucosal immunity. We discuss the roles of neutrophils in mucosal homeostasis and overview clinical susceptibilities in patients with neutrophil defects. Finally, we present concepts related to specification of neutrophil responses within specific mucosal tissue microenvironments.
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Affiliation(s)
- Lakmali M. Silva
- Oral Immunity and Infection Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892
- Proteases and Tissue Remodeling Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - Tae Sung Kim
- Oral Immunity and Infection Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892
| | - Niki M. Moutsopoulos
- Oral Immunity and Infection Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892
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25
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Uriarte SM, Hajishengallis G. Neutrophils in the periodontium: Interactions with pathogens and roles in tissue homeostasis and inflammation. Immunol Rev 2023; 314:93-110. [PMID: 36271881 PMCID: PMC10049968 DOI: 10.1111/imr.13152] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Neutrophils are of key importance in periodontal health and disease. In their absence or when they are functionally defective, as occurs in certain congenital disorders, affected individuals develop severe forms of periodontitis in early age. These observations imply that the presence of immune-competent neutrophils is essential to homeostasis. However, the presence of supernumerary or hyper-responsive neutrophils, either because of systemic priming or innate immune training, leads to imbalanced host-microbe interactions in the periodontium that culminate in dysbiosis and inflammatory tissue breakdown. These disease-provoking imbalanced interactions are further exacerbated by periodontal pathogens capable of subverting neutrophil responses to their microbial community's benefit and the host's detriment. This review attempts a synthesis of these findings for an integrated view of the neutrophils' ambivalent role in periodontal disease and, moreover, discusses how some of these concepts underpin the development of novel therapeutic approaches to treat periodontal disease.
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Affiliation(s)
- Silvia M. Uriarte
- Department of Oral Immunology and Infectious Diseases, School of Dentistry, University of Louisville, Louisville, KY, USA
| | - George Hajishengallis
- Department of Basic and Translational Sciences, Laboratory of Innate Immunity and Inflammation, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
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26
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Abstract
The principle of trained immunity represents innate immune memory due to sustained, mainly epigenetic, changes triggered by endogenous or exogenous stimuli in bone marrow (BM) progenitors (central trained immunity) and their innate immune cell progeny, thereby triggering elevated responsiveness against secondary stimuli. BM progenitors can respond to microbial and sterile signals, thereby possibly acquiring trained immunity-mediated long-lasting alterations that may shape the fate and function of their progeny, for example, neutrophils. Neutrophils, the most abundant innate immune cell population, are produced in the BM from committed progenitor cells in a process designated granulopoiesis. Neutrophils are the first responders against infectious or inflammatory challenges and have versatile functions in immunity. Together with other innate immune cells, neutrophils are effectors of peripheral trained immunity. However, given the short lifetime of neutrophils, their ability to acquire immunological memory may lie in the central training of their BM progenitors resulting in generation of reprogrammed, that is, "trained", neutrophils. Although trained immunity may have beneficial effects in infection or cancer, it may also mediate detrimental outcomes in chronic inflammation. Here, we review the emerging research area of trained immunity with a particular emphasis on the role of neutrophils and granulopoiesis.
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Affiliation(s)
- Lydia Kalafati
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
| | - Aikaterini Hatzioannou
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
| | - George Hajishengallis
- Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Triantafyllos Chavakis
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
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27
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Abdalla HB, Van Dyke TE. The impact of the soluble epoxide hydrolase cascade on periodontal tissues. FRONTIERS IN DENTAL MEDICINE 2023; 4:1129371. [PMID: 39916899 PMCID: PMC11797759 DOI: 10.3389/fdmed.2023.1129371] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 01/09/2023] [Indexed: 02/09/2025] Open
Abstract
Periodontitis is a chronic inflammatory disease with complex pathogenesis. Uncontrolled inflammation is driven by the immune system in response to accumulation of oral biofilm that leads to alveolar bone loss, bleeding, increased periodontal probing depth with loss of attachment of the connective tissues to the tooth, and ultimately, tooth loss. Soluble epoxide hydrolase (sEH) is an enzyme that converts epoxy fatty acids (EpFAs) produced by cytochrome P450 (CYP450) to an inactive diol. It has been shown that EpFAs display important features to counteract an exaggerated inflammatory process. Based upon this observation, inhibitors of sEH have been developed and are being proposed as a strategy to regulate proinflammatory lipid mediator production and the chronicity of inflammation. This mini review focuses on the impact of sEH inhibition on periodontal tissues focusing on the mechanisms involved. The interaction between Specialized Pro-Resolving Mediators and sEH inhibition emerges as a significant mechanism of action of sEH inhibitors that was not formerly appreciated and provides new insights into the role SPMs may play in prevention and treatment of periodontitis.
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Affiliation(s)
| | - Thomas E. Van Dyke
- Clinical and Translational Research, The Forsyth Institute, Cambridge, MA, United States
- Faculty of Medicine, Harvard University, Boston, MA, United States
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28
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Newman KL, Kamada N. Pathogenic associations between oral and gastrointestinal diseases. Trends Mol Med 2022; 28:1030-1039. [PMID: 35691866 PMCID: PMC9691515 DOI: 10.1016/j.molmed.2022.05.006] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 04/14/2022] [Accepted: 05/05/2022] [Indexed: 02/07/2023]
Abstract
Both periodontitis and inflammatory bowel disease (IBD) are complex chronic conditions characterized by aberrant host immune response and dysregulated microbiota. Emerging data show an association between periodontitis and IBD, including direct and indirect mechanistic links between oral and intestinal inflammation. Direct pathways include translocation of proinflammatory microbes from the oral cavity to the gut and immune priming. Indirect pathways involve systemic immune activation with possible nonspecific effects on the gut. There are limited data on the effects of periodontal disease treatment on IBD course and vice versa, but early reports suggest that treatment of periodontitis decreases systemic immune activation and that treatment of IBD is associated with periodontitis healing, underscoring the importance of recognizing and treating both conditions.
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Affiliation(s)
- Kira L Newman
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Nobuhiko Kamada
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
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29
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Irwandi RA, Chiesa ST, Hajishengallis G, Papayannopoulos V, Deanfield JE, D’Aiuto F. The Roles of Neutrophils Linking Periodontitis and Atherosclerotic Cardiovascular Diseases. Front Immunol 2022; 13:915081. [PMID: 35874771 PMCID: PMC9300828 DOI: 10.3389/fimmu.2022.915081] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 06/13/2022] [Indexed: 01/02/2023] Open
Abstract
Inflammation plays a crucial role in the onset and development of atherosclerosis. Periodontitis is a common chronic disease linked to other chronic inflammatory diseases such as atherosclerotic cardiovascular disease (ASCVD). The mechanistic pathways underlying this association are yet to be fully understood. This critical review aims at discuss the role of neutrophils in mediating the relationship between periodontitis and ASCVD. Systemic inflammation triggered by periodontitis could lead to adaptations in hematopoietic stem and progenitor cells (HSPCs) resulting in trained granulopoiesis in the bone marrow, thereby increasing the production of neutrophils and driving the hyper-responsiveness of these abundant innate-immune cells. These alterations may contribute to the onset, progression, and complications of atherosclerosis. Despite the emerging evidence suggesting that the treatment of periodontitis improves surrogate markers of cardiovascular disease, the resolution of periodontitis may not necessarily reverse neutrophil hyper-responsiveness since the hyper-inflammatory re-programming of granulopoiesis can persist long after the inflammatory inducers are removed. Novel and targeted approaches to manipulate neutrophil numbers and functions are warranted within the context of the treatment of periodontitis and also to mitigate its potential impact on ASCVD.
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Affiliation(s)
- Rizky A. Irwandi
- Periodontology Unit, UCL Eastman Dental Institute, University College London, London, United Kingdom
| | - Scott T. Chiesa
- UCL Institute of Cardiovascular Science, University College London, London, United Kingdom
| | - George Hajishengallis
- Department of Basic & Translational Sciences, Laboratory of Innate Immunity & Inflammation, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | | | - John E. Deanfield
- UCL Institute of Cardiovascular Science, University College London, London, United Kingdom
| | - Francesco D’Aiuto
- Periodontology Unit, UCL Eastman Dental Institute, University College London, London, United Kingdom
- *Correspondence: Francesco D’Aiuto,
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30
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Zenobia C, Darveau RP. Does Oral Endotoxin Contribute to Systemic Inflammation? FRONTIERS IN ORAL HEALTH 2022; 3:911420. [PMID: 35677024 PMCID: PMC9169450 DOI: 10.3389/froh.2022.911420] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Accepted: 04/29/2022] [Indexed: 12/27/2022] Open
Abstract
The oral microbiome, with a unique emphasis on Porphyromonas gingivalis has been associated with a constellation of inflammatory diseases such as cardiovascular disease, rheumatoid arthritis, Alzheimer's disease, type II diabetes, and non-alcoholic associated fatty liver disease. Periodontal disease has also been shown to induce "leaky gut" leading to metabolic endotoxemia. Several recent studies investigating the habitants of the blood microbiome have found the majority of species appear to be derived from oral and skin bacterial communities in otherwise healthy individuals. Many of the same pathologies associated with perturbations of oral health, such as cardiovascular disease, show alterations to the composition of the blood microbiome as well as circulating neutrophil phenotypes. Gingival inflammation is associated with activated blood neutrophil phenotypes that can exacerbate a distal inflammatory insult which may explain the connection between oral and systemic inflammatory conditions. While in the oral cavity, neutrophils encounter oral microbes that are adept in manipulating neutrophil activity which can re-enter the vasculature thereafter. Endotoxin from oral microbes can differ significantly depending on bacterial community and state of oral health to alter cellular LPS tolerance mechanisms which may contribute to the primed neutrophil phenotype seen in periodontitis and provide a mechanism by which the oral-microbes can affect systemic health outcomes. This review synthesizes the studies between inflammatory diseases and oral health with emphasis on microbiome and corresponding lipopolysaccharides in immune tolerance and activation.
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Affiliation(s)
| | - Richard P. Darveau
- Departments of Periodontology and Microbiology, University of Washington, Seattle, WA, United States
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31
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Impact of Gingivitis on Circulating Neutrophil Reactivity and Gingival Crevicular Fluid Inflammatory Proteins. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:ijerph19106339. [PMID: 35627876 PMCID: PMC9141451 DOI: 10.3390/ijerph19106339] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 05/17/2022] [Accepted: 05/20/2022] [Indexed: 11/27/2022]
Abstract
Gingivitis is an extremely common oral inflammatory condition and can be induced in humans using an acute 21-day experimental gingivitis model. Neutrophils are known to be highly prevalent in the gingival crevice during gingival inflammation; however, the effect of gingivitis and the associated biofilm on peripheral blood neutrophils (PBN) is not well characterised. Thus, the aim of this study was to examine the impact of inflammation induced by experimental gingivitis and its resolution upon the function of PBN. Fifteen systemically healthy volunteers undertook a split-mouth 21-day experimental gingivitis study followed by a resolution phase of 14 days. PBN function, including reactive oxygen species (ROS) production, neutrophil extracellular trap (NET) release, directional chemotactic accuracy and expression of host mediators in gingival crevicular fluid (GCF), were measured at baseline (day 0), on day 21 and on day 35. NET formation and ROS production were significantly elevated at day 21. Chemotactic speed was also elevated in response to bacterial peptide fMLP at day 21. At day 35, ROS production in response to an Fcgamma stimulant, opsonised Staphylococcus aureus, remained elevated. The data presented suggest a lasting biological impact of the experimental gingivitis on PBN function even after clinical symptoms have abated.
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32
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Li X, Wang H, Yu X, Saha G, Kalafati L, Ioannidis C, Mitroulis I, Netea MG, Chavakis T, Hajishengallis G. Maladaptive innate immune training of myelopoiesis links inflammatory comorbidities. Cell 2022; 185:1709-1727.e18. [PMID: 35483374 PMCID: PMC9106933 DOI: 10.1016/j.cell.2022.03.043] [Citation(s) in RCA: 144] [Impact Index Per Article: 48.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 02/22/2022] [Accepted: 03/30/2022] [Indexed: 12/30/2022]
Abstract
Bone marrow (BM)-mediated trained innate immunity (TII) is a state of heightened immune responsiveness of hematopoietic stem and progenitor cells (HSPC) and their myeloid progeny. We show here that maladaptive BM-mediated TII underlies inflammatory comorbidities, as exemplified by the periodontitis-arthritis axis. Experimental-periodontitis-related systemic inflammation in mice induced epigenetic rewiring of HSPC and led to sustained enhancement of production of myeloid cells with increased inflammatory preparedness. The periodontitis-induced trained phenotype was transmissible by BM transplantation to naive recipients, which exhibited increased inflammatory responsiveness and disease severity when subjected to inflammatory arthritis. IL-1 signaling in HSPC was essential for their maladaptive training by periodontitis. Therefore, maladaptive innate immune training of myelopoiesis underlies inflammatory comorbidities and may be pharmacologically targeted to treat them via a holistic approach.
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Affiliation(s)
- Xiaofei Li
- Department of Basic and Translational Sciences, Laboratory of Innate Immunity and Inflammation, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Hui Wang
- Department of Basic and Translational Sciences, Laboratory of Innate Immunity and Inflammation, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Xiang Yu
- Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China; Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Gundappa Saha
- Department of Basic and Translational Sciences, Laboratory of Innate Immunity and Inflammation, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Lydia Kalafati
- Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, Technische Universität Dresden, 01307 Dresden, Germany
| | - Charalampos Ioannidis
- Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, Technische Universität Dresden, 01307 Dresden, Germany
| | - Ioannis Mitroulis
- Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, Technische Universität Dresden, 01307 Dresden, Germany; First Department of Internal Medicine and Department of Haematology, Democritus University of Thrace, 681 00 Alexandroupolis, Greece
| | - Mihai G Netea
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen 6525 XZ, the Netherlands; Department of Immunology and Metabolism, Life and Medical Science Institute, University of Bonn, 53115 Bonn, Germany
| | - Triantafyllos Chavakis
- Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, Technische Universität Dresden, 01307 Dresden, Germany; Centre for Cardiovascular Science, University of Edinburgh, Edinburgh EH16 4TJ, UK.
| | - George Hajishengallis
- Department of Basic and Translational Sciences, Laboratory of Innate Immunity and Inflammation, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
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Albuquerque-Souza E, Sahingur SE. Periodontitis, chronic liver diseases, and the emerging oral-gut-liver axis. Periodontol 2000 2022; 89:125-141. [PMID: 35244954 PMCID: PMC9314012 DOI: 10.1111/prd.12427] [Citation(s) in RCA: 59] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The liver carries out a wide range of functions ranging from the control of metabolites, nutrient storage, and detoxification to immunosurveillance. While inflammation is essential for the tissue remodeling and maintenance of homeostasis and normal liver physiology, constant exposure to dietary and microbial products creates a niche for potentially prolonged immune activation and unresolved inflammation in susceptible host. Failure to restrain inflammation can lead to development of chronic liver diseases characterized by fibrosis, cirrhosis and eventually liver failure. The liver maintains close interactions with numerous organs which can influence its metabolism and physiology. It is also known that oral cavity microenvironment can influence the physiological conditions of other organs and emerging evidence implicates that this could be true for the liver as well. Presence of chronic inflammation and dysbiotic microbiota is a common feature leading to clinical pathology both in periodontitis and chronic liver diseases (CLDs). In fact, known CLDs appear to have some relationship with periodontitis, which impacts the onset or progression of these conditions in a bidirectional crosstalk. In this review, we explore the emerging association between oral‐gut‐liver axis focusing on periodontitis and common CLDs including nonalcoholic fatty liver disease, chronic viral hepatitis, liver cirrhosis, and hepatocellular cancer. We highlight the immune pathways and oral microbiome interactions which can link oral cavity and liver health and offer perspectives for future research.
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Affiliation(s)
- Emmanuel Albuquerque-Souza
- Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Sinem E Sahingur
- Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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34
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Hajishengallis G, Li X, Divaris K, Chavakis T. Maladaptive trained immunity and clonal hematopoiesis as potential mechanistic links between periodontitis and inflammatory comorbidities. Periodontol 2000 2022; 89:215-230. [PMID: 35244943 DOI: 10.1111/prd.12421] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Periodontitis is bidirectionally associated with systemic inflammatory disorders. The prevalence and severity of this oral disease and linked comorbidities increases with aging. Here, we review two newly emerged concepts, trained innate immunity (TII) and clonal hematopoiesis of indeterminate potential (CHIP), which together support a potential hypothesis on how periodontitis affects and is affected by comorbidities and why the susceptibility to periodontitis and comorbidities increases with aging. Given that chronic diseases are largely triggered by the action of inflammatory immune cells, modulation of their bone marrow precursors, the hematopoietic stem and progenitor cells (HSPCs), may affect multiple disorders that emerge as comorbidities. Such alterations in HSPCs can be mediated by TII and/or CHIP, two non-mutually exclusive processes sharing a bias for enhanced myelopoiesis and production of innate immune cells with heightened proinflammatory potential. TII is a state of elevated immune responsiveness based on innate immune (epigenetic) memory. Systemic inflammation can initiate TII in the bone marrow via sustained rewiring of HSPCs, which thereby display a skewing toward the myeloid lineage, resulting in generation of hyper-reactive or "trained" myeloid cells. CHIP arises from aging-related somatic mutations in HSPCs, which confer a survival and proliferation advantage to the mutant HSPCs and give rise to an outsized fraction of hyper-inflammatory mutant myeloid cells in the circulation and tissues. This review discusses emerging evidence that supports the notion that TII and CHIP may underlie a causal and age-related association between periodontitis and comorbidities. A holistic mechanistic understanding of the periodontitis-systemic disease connection may offer novel diagnostic and therapeutic targets for treating inflammatory comorbidities.
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Affiliation(s)
- George Hajishengallis
- Department of Basic and Translational Sciences, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Xiaofei Li
- Department of Basic and Translational Sciences, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Kimon Divaris
- Division of Pediatrics and Public Health, Adams School of Dentistry, University of North Carolina, Chapel Hill, NC, USA.,Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA
| | - Triantafyllos Chavakis
- Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
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35
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Metcalfe S, Anselmi N, Escobar A, Visser MB, Kay JG. Innate Phagocyte Polarization in the Oral Cavity. Front Immunol 2022; 12:768479. [PMID: 35069541 PMCID: PMC8770816 DOI: 10.3389/fimmu.2021.768479] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 12/14/2021] [Indexed: 12/24/2022] Open
Abstract
The oral cavity is a complex environment constantly exposed to antigens from food and the oral microbiota. Innate immune cells play an essential role in maintaining health and homeostasis in the oral environment. However, these cells also play a significant role in disease progression. This review will focus on two innate phagocytes in the oral cavity: macrophages and neutrophils, and examine their roles during homeostasis and disease development, with a focus on periodontal disease and cancer. Macrophages have a well-known ability to polarize and be activated towards a variety of phenotypes. Several studies have found that macrophages’ polarization changes can play an essential role in maintaining health in the oral cavity and contribute to disease. Recent data also finds that neutrophils display phenotypic heterogeneity in the oral cavity. In both cases, we focus on what is known about how these cellular changes alter these immune cells’ interactions with the oral microbiota, including how such changes can lead to worsening, rather than improving, disease states.
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Affiliation(s)
- Sarah Metcalfe
- Department of Oral Biology, School of Dental Medicine, University at Buffalo, Buffalo, NY, United States
| | - Natalie Anselmi
- Department of Oral Biology, School of Dental Medicine, University at Buffalo, Buffalo, NY, United States
| | - Alejandro Escobar
- Instituto de Investigación en Ciencias Odontológicas, Facultad de Odontología, Universidad de Chile, Santiago, Chile
| | - Michelle B Visser
- Department of Oral Biology, School of Dental Medicine, University at Buffalo, Buffalo, NY, United States
| | - Jason G Kay
- Department of Oral Biology, School of Dental Medicine, University at Buffalo, Buffalo, NY, United States
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36
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Irwandi RA, Kuswandani SO, Harden S, Marletta D, D'Aiuto F. Circulating inflammatory cell profiling and periodontitis: A systematic review and meta-analysis. J Leukoc Biol 2022; 111:1069-1096. [PMID: 35199874 DOI: 10.1002/jlb.5ru1021-524r] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 01/14/2022] [Accepted: 01/31/2022] [Indexed: 12/13/2022] Open
Abstract
Inflammation is a key driver of common noncommunicable diseases. Among common triggers of inflammation, chronic gingival inflammation (periodontitis) triggers a consistent humoral host inflammatory response, but little is known on its impact on circulating inflammatory cell profiles. We aimed to systematically appraise all the evidence linking periodontitis and its treatment to circulating inflammatory cell profiles. From 6 databases, 157 studies were eligible for qualitative synthesis and 29 studies for meta-analysis. Our meta-analysis showed that participants with periodontitis exhibited a significant mean increase in circulating CD4+ , CD4+ CD45RO+ , IFNγ-expressing CD4+ and CD8+ T cells, CD19+ CD27+ and CD5+ B cells, CD14+ CD16+ monocytes, and CD16+ neutrophils but decrease in CD8+ T and CD14++ CD16- monocytes. Our qualitative synthesis revealed that peripheral blood neutrophils of patients with periodontitis consistently showed elevated production of reactive oxygen species (ROS) when compared with those of healthy controls. Some evidence suggested that the treatment of periodontitis reversed the exaggerated ROS production, but limited and inconclusive data were found on several circulating inflammatory cell profiling. We conclude that periodontitis and its treatment are associated with minor but consistent alterations in circulating inflammatory cell profiles. These changes could represent key mechanisms explaining the association of periodontitis with other comorbidities such as cardiovascular disease, diabetes, and rheumatoid arthritis.
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Affiliation(s)
- Rizky A Irwandi
- Periodontology Unit, Eastman Dental Institute, University College London, London, United Kingdom
| | - Sandra O Kuswandani
- Periodontology Unit, Eastman Dental Institute, University College London, London, United Kingdom.,Department of Periodontology, Faculty of Dentistry, Universitas Indonesia, Jakarta, Indonesia
| | - Simon Harden
- Department of Statistical Science, University College London, London, United Kingdom
| | - Debora Marletta
- Cruciform Hub, University College London, London, United Kingdom
| | - Francesco D'Aiuto
- Periodontology Unit, Eastman Dental Institute, University College London, London, United Kingdom
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Barutta F, Bellini S, Durazzo M, Gruden G. Novel Insight into the Mechanisms of the Bidirectional Relationship between Diabetes and Periodontitis. Biomedicines 2022; 10:biomedicines10010178. [PMID: 35052857 PMCID: PMC8774037 DOI: 10.3390/biomedicines10010178] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Revised: 01/13/2022] [Accepted: 01/14/2022] [Indexed: 02/01/2023] Open
Abstract
Periodontitis and diabetes are two major global health problems despite their prevalence being significantly underreported and underestimated. Both epidemiological and intervention studies show a bidirectional relationship between periodontitis and diabetes. The hypothesis of a potential causal link between the two diseases is corroborated by recent studies in experimental animals that identified mechanisms whereby periodontitis and diabetes can adversely affect each other. Herein, we will review clinical data on the existence of a two-way relationship between periodontitis and diabetes and discuss possible mechanistic interactions in both directions, focusing in particular on new data highlighting the importance of the host response. Moreover, we will address the hypothesis that trained immunity may represent the unifying mechanism explaining the intertwined association between diabetes and periodontitis. Achieving a better mechanistic insight on clustering of infectious, inflammatory, and metabolic diseases may provide new therapeutic options to reduce the risk of diabetes and diabetes-associated comorbidities.
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38
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COVID-19 Pandemic and Periodontal Practice: The Immunological, Clinical, and Economic Points of View. BIOMED RESEARCH INTERNATIONAL 2022; 2022:3918980. [PMID: 35047633 PMCID: PMC8763038 DOI: 10.1155/2022/3918980] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Accepted: 12/24/2021] [Indexed: 11/17/2022]
Abstract
The recent global health problem, COVID-19, has had far-reaching impacts on lifestyles. Although many effective WHO-approved vaccines have been produced that have reduced the spread and severity of the disease, it appears to persist in humans for a long time and possibly forever as everyday it turns out to have new mutations. COVID-19 involves the lungs and other organs primarily through cytokine storms, which have been implicated in many other inflammatory disorders, including periodontal diseases. COVID-19 is in a close association with dental and periodontal practice from two respects: first, repeated mandatory lockdowns have reduced patient referrals to dentists and limited the dental and periodontal procedures to emergency treatments, whereas it is important to recognize the oral manifestations of COVID-19 as well as the influence of oral and periodontal disease on the severity of COVID-19. Second, dentistry is one of the high-risk professions in terms of close contact with unmasked individuals, necessitating redefining the principles of infection control. The pressures of the economic recession on patients as well as dentists add to the difficulty of resuming elective dental services. Therefore, this study is divided into two parts corresponding to what mentioned above: the first part examines the clinical and immunological associations between COVID-19 and periodontal and oral diseases, and the second part delineates the measures needed to control the disease transmission in dental clinics as well as the economic impact of the pandemic era on dental services.
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39
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Periodontal health, neutrophil activity and cardiovascular health in captive chimpanzees. Arch Oral Biol 2021; 134:105342. [PMID: 34942432 DOI: 10.1016/j.archoralbio.2021.105342] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 11/16/2021] [Accepted: 12/14/2021] [Indexed: 12/23/2022]
Abstract
OBJECTIVE To investigate the association of dental and cardiac disease in a cohort of captive chimpanzees DESIGN: 12 captive chimpanzees underwent periodontal and cardiac examinations under anaesthesia during a relocation to a new enclosure. Blood samples were taken for analysis of circulating markers of cardiac health, nutritional status and isolation of neutrophils for functional assays. They were then observed for three years for signs of heart disease. RESULTS Although the chimpanzees displayed large quantities of supragingival plaque, they had low bleeding scores. Peripheral blood neutrophils responded to innate and adaptive immune stimuli. In the follow up period two animals died and post mortem confirmed heart disease. Levels of NT-proBNP were found to be high in chimpanzees that died from heart disease. CONCLUSIONS Whilst there appeared to be a correlation between probing depth and age, there appeared to be no correlation between dental data and heart data in this cohort.
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Rawat K, Syeda S, Shrivastava A. Hyperactive neutrophils infiltrate vital organs of tumor bearing host and contribute to gradual systemic deterioration via upregulated NE, MPO and MMP-9 activity. Immunol Lett 2021; 241:35-48. [PMID: 34890699 DOI: 10.1016/j.imlet.2021.12.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 11/27/2021] [Accepted: 12/06/2021] [Indexed: 12/15/2022]
Abstract
Cancer is known to have systemic impact by targeting various organs that ultimately compromises the overall physiology of the host. Several reports have demonstrated the role of neutrophils in cancer wherein the focus has been drawn on the elevated neutrophil count in blood or at tumor loci. However, their role in mediating systemic effects during cancer progression has not been deciphered so far. Therefore, it is worthwhile to explore whether and how neutrophils contribute to systemic deterioration in cancer. To discern their systemic role, we evaluated neutrophil count and function at different stages of tumor growth in Dalton's Lymphoma mice model. Notably, our results displayed a gradual increase in Ly6G+ neutrophils in peripheral blood and their infiltration in vital organs including liver, lungs, spleen, kidney, lymph nodes and peritoneum of tumor bearing host. We showed remarkable alterations in histoarchitecture and serum enzyme levels that aggravated with tumor progression. We next examined neutrophil function by assessing its granular cargoes including neutrophil elastase (NE), myeloperoxidase (MPO), and matrix metalloproteinases (MMP-8 and MMP-9). Interestingly, blood neutrophils of tumor bearing mice exhibited a marked change in morphology with gradual increase in NE and MPO expression with tumor growth. In addition, we observed upregulated expression of NE, MPO, MMP-8 and MMP-9 in the vital organs of tumor bearing host. Taken together, our results demonstrate heightened infiltration and function of neutrophils in vital organs of tumor bearing host which possibly account for gradual systemic deterioration during cancer progression. Our findings thus implicate neutrophils as a potential therapeutic target that may help to reduce the overall fatality rate of cancer.
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Affiliation(s)
- Kavita Rawat
- Department of Zoology, University of Delhi, Delhi 110007, India
| | - Saima Syeda
- Department of Zoology, University of Delhi, Delhi 110007, India
| | - Anju Shrivastava
- Department of Zoology, University of Delhi, Delhi 110007, India.
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41
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Wang Y, Feng F, Zheng P, Wang L, Wang Y, Lv Y, Shen L, Li K, Feng T, Chen Y, Liu Z, Yao Y. Dysregulated lncRNA and mRNA may promote the progression of ischemic stroke via immune and inflammatory pathways: results from RNA sequencing and bioinformatics analysis. Genes Genomics 2021; 44:97-108. [PMID: 34699043 PMCID: PMC8546200 DOI: 10.1007/s13258-021-01173-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 09/27/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Long non-coding RNAs (lncRNAs) are widely involved in gene transcription regulation and which act as epigenetic modifiers in many diseases. OBJECTIVE To determine whether lncRNAs are involved in ischemic stroke (IS), we analyzed the expression profile of lncRNAs and mRNAs in IS. METHODS RNA sequencing was performed on the blood of three pairs of IS patients and healthy controls. Differential expression analysis was used to identify differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs). Based on the co-expression relationships between lncRNA and mRNA, a series of bioinformatics analysis including GO and KEGG enrichment analysis and PPI analysis, were conducted to predict the function of lncRNA. RESULTS RNA sequencing produced a total of 5 DElncRNAs and 144 DEmRNAs. Influenza A pathway and Herpes simplex infection pathway were the most significant pathways. EP300 and NFKB1 were the most important target proteins, and Human leucocyte antigen (HLA) family were the key genes in IS. CONCLUSIONS Analysis of this study revealed that dysregulated lncRNAs in IS may lead to IS by affecting the immune and inflammation system.
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Affiliation(s)
- Yingshuang Wang
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, 130021, China
| | - Feifei Feng
- Jilin Province of Jilin Combine Traditional Chinese and Western Medicine Hospital, Jilin, 132000, China
| | - Pingping Zheng
- Futian District Center for Disease Prevention and Control, Shenzhen, 518040, China
| | - Lijuan Wang
- Department of Neurology, The Neuroscience Center, The First Hospital of Jilin University, Jilin University, Changchun, 130021, China
| | - Yanjun Wang
- Nursing Department, The Second Hospital of Jilin University, Changchun, 130021, Jilin, China
| | - Yaogai Lv
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, 130021, China
| | - Li Shen
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, 130021, China
| | - Kexin Li
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, 130021, China
| | - Tianyu Feng
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, 130021, China
| | - Yang Chen
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, 130021, China
| | - Zhigang Liu
- Department of Pain Management, The Second Hospital of Jilin University, No.218, Ziqiang Street, Nanguan District, Changchun, 130041, Jilin, China.
| | - Yan Yao
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, 130021, China.
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Mouradian W, Lee J, Wilentz J, Somerman M. A Perspective: Integrating Dental and Medical Research Improves Overall Health. FRONTIERS IN DENTAL MEDICINE 2021. [DOI: 10.3389/fdmed.2021.699575] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The past decade has seen marked increases in research findings identifying oral-systemic links. Yet, much of dental research remains poorly integrated with mainstream biomedical research. The historic separation of dentistry from medicine has led to siloed approaches in education, research and practice, ultimately depriving patients, providers, and policy makers of findings that could benefit overall health and well-being. These omissions amount to lost opportunities for risk assessment, diagnosis, early intervention and prevention of disease, increasing cost and contributing to a fragmented and inefficient healthcare delivery system. This perspective provides examples where fostering interprofessional research collaborations has advanced scientific understanding and yielded clinical benefits. In contrast are examples where failure to include dental research findings has limited progress and led to adverse health outcomes. The impetus to overcome the dental-medical research divide gains further urgency today in light of the coronavirus pandemic where contributions that dental research can make to understanding the pathophysiology of the SARS-CoV-2 virus and in diagnosing and preventing infection are described. Eliminating the research divide will require collaborative and trans-disciplinary research to ensure incorporation of dental research findings in broad areas of biomedical research. Enhanced communication, including interoperable dental/medical electronic health records and educational efforts will be needed so that the public, health care providers, researchers, professional schools, organizations, and policymakers can fully utilize oral health scientific information to meet the overall health needs of the public.
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Wang L, He Y, Ning W. Role of enhancer of zeste homolog 2 in osteoclast formation and periodontitis development by downregulating microRNA-101-regulated VCAM-1. J Tissue Eng Regen Med 2021; 15:534-545. [PMID: 33686766 DOI: 10.1002/term.3187] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 02/03/2021] [Indexed: 02/06/2023]
Abstract
The enhancer of zeste homolog 2 (EZH2) represents a potential target for periodontitis treatment; however, its role in the development of periodontitis remains unclear. The current study aimed to elucidate the role of EZH2 in osteoclasts (OCs) growth as well as the mechanism underpinning the related process. The potential interaction among EZH2, microRNA-101 (miR-101), and vascular cell adhesion molecule 1 (VCAM-1) was evaluated using chromatin immunoprecipitation and dual-luciferase reporter gene assay. The expressions of EZH2 and miR-101 in OCs were examined by Western blot analysis and reverse transcription squantitative polymerase chain reaction. Loss- and gain-function assays were then performed to determine the role of EZH2/miR-101/VCAM-1 in periodontitis and OCs proliferation, followed by OC growth and proliferation detected using tartrate resistant acid phosphatase (TRAP) and 5-ethynyl-2'-deoxyuridine staining. Enzyme-linked immunoassay was conducted to determine the expression of interleukin 1β (IL-1β) and tumor necrosis factor-α (TNF-α). A periodontitis rat model was established to investigate the effect of EZH2 and VCAM-1 in vivo. EZH2 was overexpressed, while miR-101 was downregulated in the OCs of periodontitis. Silencing of EZH2, VCAM-1 repression, or miR-101 elevation suppressed the growth and proliferation of OC while acting to encumber the release of IL-1β and TNF-α. EZH2 negatively targeted miR-101, while miR-101 negatively targeted VCAM-1. Moreover, silencing of EZH2 or VCAM-1 was observed to attenuate periodontitis which was evidenced by an increase in BMD, BV/TV, and BS/BV as well as reduction in TRAP and cathepsin K in vivo. Taken together, the key findings of the current study demonstrate that EZH2 knockdown inhibited OC formation by elevating the expression of miR-101 via suppression of VCAM-1, ultimately attenuating periodontitis.
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Affiliation(s)
- Li Wang
- Department of Periodontology, The First Affiliated Hospital of Harbin Medical University, School of Stomatology, Harbin Medical University, Harbin, China
| | - Yanyan He
- Department of Stomatology, The First Affiliated Hospital of Zhejiang University, Hangzhou, China
| | - Wanchen Ning
- Department of Preventive Dentistry and Periodontology, Ludwig-Maximilians University of Munich, Munich, Germany
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Cardoso EOC, Fine N, Glogauer M, Johnson F, Goldberg M, Golub LM, Tenenbaum HC. The Advent of COVID-19; Periodontal Research Has Identified Therapeutic Targets for Severe Respiratory Disease; an Example of Parallel Biomedical Research Agendas. FRONTIERS IN DENTAL MEDICINE 2021. [DOI: 10.3389/fdmed.2021.674056] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The pathophysiology of SARS-CoV-2 infection is characterized by rapid virus replication and aggressive inflammatory responses that can lead to acute respiratory distress syndrome (ARDS) only a few days after the onset of symptoms. It is suspected that a dysfunctional immune response is the main cause of SARS-CoV-2 infection-induced lung destruction and mortality due to massive infiltration of hyperfunctional neutrophils in these organs. Similarly, neutrophils are recruited constantly to the oral cavity to combat microorganisms in the dental biofilm and hyperfunctional neutrophil phenotypes cause destruction of periodontal tissues when periodontitis develops. Both disease models arise because of elevated host defenses against invading organisms, while concurrently causing host damage/disease when the immune cells become hyperfunctional. This represents a clear nexus between periodontal and medical research. As researchers begin to understand the link between oral and systemic diseases and their potential synergistic impact on general health, we argue that translational research from studies in periodontology must be recognized as an important source of information that might lead to different therapeutic options which can be effective for the management of both oral and non-oral diseases. In this article we connect concepts from periodontal research on oral inflammation while exploring host modulation therapy used for periodontitis as a potential strategy for the prevention of ARDS a deadly outcome of COVID-19. We suggest that host modulation therapy, although developed initially for management of periodontitis, and which inhibits proteases, cytokines, and the oxidative stress that underlie ARDS, will provide an effective and safe treatment for COVID-19.
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45
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Alvarez C, Abdalla H, Sulliman S, Rojas P, Wu YC, Almarhoumi R, Huang RY, Galindo M, Vernal R, Kantarci A. RvE1 Impacts the Gingival Inflammatory Infiltrate by Inhibiting the T Cell Response in Experimental Periodontitis. Front Immunol 2021; 12:664756. [PMID: 34012448 PMCID: PMC8126725 DOI: 10.3389/fimmu.2021.664756] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 04/16/2021] [Indexed: 12/13/2022] Open
Abstract
Periodontitis is a chronic inflammatory disease associated with the formation of dysbiotic plaque biofilms and characterized by the progressive destruction of the alveolar bone. The transition from health to disease is characterized by a shift in periodontal immune cell composition, from mostly innate (neutrophils) to adaptive (T lymphocytes) immune responses. Resolvin E1 (RvE1) is a specialized pro-resolution mediator (SPMs), produced in response to inflammation, to enhance its resolution. Previous studies have indicated the therapeutic potential of RvE1 in periodontal disease; however, the impact of RvE1 in the microbial-elicited osteoclastogenic immune response remains uncharacterized in vivo. In the present study, we studied the impact of RvE1 on the gingival inflammatory infiltrate formation during periodontitis in a mouse model. First, we characterized the temporal-dependent changes of the main immune cells infiltrating the gingiva by flow cytometry. Then, we evaluated the impact of early or delayed RvE1 administration on the gingival immune infiltration and cervical lymph nodes composition. We observed a consistent inhibitory outcome on T cells -particularly effector T cells- and a protective effect on regulatory T cells (Tregs). Our data further demonstrated the wide range of actions of RvE1, its preventive role in the establishment of the adaptive immune response during inflammation, and bone protective capacity.
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Affiliation(s)
| | - Henrique Abdalla
- Forsyth Institute, Cambridge, MA, United States.,Laboratory of Neuroimmune Interface of Pain Research, Faculdade São Leopoldo Mandic, Instituto de Pesquisas São Leopoldo Mandic, Campinas, Brazil
| | - Salwa Sulliman
- Forsyth Institute, Cambridge, MA, United States.,Department of Clinical Dentistry, Center for Clinical Dental Research, University of Bergen, Bergen, Norway
| | - Paola Rojas
- Forsyth Institute, Cambridge, MA, United States
| | - Yu-Chiao Wu
- Forsyth Institute, Cambridge, MA, United States.,Harvard School of Dental Medicine, Boston, MA, United States
| | - Rawan Almarhoumi
- Forsyth Institute, Cambridge, MA, United States.,Harvard School of Dental Medicine, Boston, MA, United States
| | - Ren-Yeong Huang
- Forsyth Institute, Cambridge, MA, United States.,School of Dentistry, National Defense Medical Center, Taipei, Taiwan
| | - Mario Galindo
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, Universidad de Chile, Santiago, Chile.,Millennium Institute on Immunology and Immunotherapy, Faculty of Medicine, University of Chile, Santiago, Chile
| | - Rolando Vernal
- Periodontal Biology Laboratory, Dentistry Faculty, Universidad de Chile, Santiago, Chile
| | - Alpdogan Kantarci
- Forsyth Institute, Cambridge, MA, United States.,Harvard School of Dental Medicine, Boston, MA, United States
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Jiang Q, Zhao Y, Shui Y, Zhou X, Cheng L, Ren B, Chen Z, Li M. Interactions Between Neutrophils and Periodontal Pathogens in Late-Onset Periodontitis. Front Cell Infect Microbiol 2021; 11:627328. [PMID: 33777839 PMCID: PMC7994856 DOI: 10.3389/fcimb.2021.627328] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 02/03/2021] [Indexed: 02/05/2023] Open
Abstract
Late-onset periodontitis is associated with a series of inflammatory reactions induced by periodontal pathogens, such as Porphyromonas gingivalis, a keystone pathogen involved in periodontitis. Neutrophils are the most abundant leukocytes in the periodontal pocket/gingival crevice and inflamed periodontal tissues. They form a “wall” between the dental plaque and the junctional epithelium, preventing microbial invasion. The balance between neutrophils and the microbial community is essential to periodontal homeostasis. Excessive activation of neutrophils in response to periodontal pathogens can induce tissue damage and lead to periodontitis persistence. Therefore, illuminating the interactions between neutrophils and periodontal pathogens is critical for progress in the field of periodontitis. The present review aimed to summarize the interactions between neutrophils and periodontal pathogens in late-onset periodontitis, including neutrophil recruitment, neutrophil mechanisms to clear the pathogens, and pathogen strategies to evade neutrophil-mediated elimination of bacteria. The recruitment is a multi-step process, including tethering and rolling, adhesion, crawling, and transmigration. Neutrophils clear the pathogens mainly by phagocytosis, respiratory burst responses, degranulation, and neutrophil extracellular trap (NET) formation. The mechanisms that pathogens activate to evade neutrophil-mediated killing include impairing neutrophil recruitment, preventing phagocytosis, uncoupling killing from inflammation, and resistance to ROS, degranulation products, and NETs.
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Affiliation(s)
- Qingsong Jiang
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, National Clinical Research Center for Oral Diseases, Sichuan University, Chengdu, China
| | - Yuxi Zhao
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, National Clinical Research Center for Oral Diseases, Sichuan University, Chengdu, China
| | - Yusen Shui
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, National Clinical Research Center for Oral Diseases, Sichuan University, Chengdu, China
| | - Xuedong Zhou
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, National Clinical Research Center for Oral Diseases, Sichuan University, Chengdu, China
| | - Lei Cheng
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, National Clinical Research Center for Oral Diseases, Sichuan University, Chengdu, China
| | - Biao Ren
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, National Clinical Research Center for Oral Diseases, Sichuan University, Chengdu, China
| | - Zhu Chen
- Department of Conservative Dentistry and Endodontics, Guiyang Hospital of Stomatology, Guiyang, China
| | - Mingyun Li
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, National Clinical Research Center for Oral Diseases, Sichuan University, Chengdu, China
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Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities. Nat Rev Immunol 2021; 21:426-440. [PMID: 33510490 PMCID: PMC7841384 DOI: 10.1038/s41577-020-00488-6] [Citation(s) in RCA: 779] [Impact Index Per Article: 194.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/09/2020] [Indexed: 12/13/2022]
Abstract
Periodontitis, a major inflammatory disease of the oral mucosa, is epidemiologically associated with other chronic inflammation-driven disorders, including cardio-metabolic, neurodegenerative and autoimmune diseases and cancer. Emerging evidence from interventional studies indicates that local treatment of periodontitis ameliorates surrogate markers of comorbid conditions. The potential causal link between periodontitis and its comorbidities is further strengthened by recent experimental animal studies establishing biologically plausible and clinically consistent mechanisms whereby periodontitis could initiate or aggravate a comorbid condition. This multi-faceted ‘mechanistic causality’ aspect of the link between periodontitis and comorbidities is the focus of this Review. Understanding how certain extra-oral pathologies are affected by disseminated periodontal pathogens and periodontitis-associated systemic inflammation, including adaptation of bone marrow haematopoietic progenitors, may provide new therapeutic options to reduce the risk of periodontitis-associated comorbidities. Periodontitis has been causally linked to the development of other chronic inflammatory diseases outside the oral mucosa. In this Review, George Hajishengallis and Triantafyllos Chavakis consider the molecular basis of these links.
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Miralda I, Uriarte SM. Periodontal Pathogens' strategies disarm neutrophils to promote dysregulated inflammation. Mol Oral Microbiol 2020; 36:103-120. [PMID: 33128827 PMCID: PMC8048607 DOI: 10.1111/omi.12321] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 10/16/2020] [Accepted: 10/28/2020] [Indexed: 12/26/2022]
Abstract
Periodontitis is an irreversible, chronic inflammatory disease where inflammophilic pathogenic microbial communities accumulate in the gingival crevice. Neutrophils are a major component of the innate host response against bacterial challenge, and under homeostatic conditions, their microbicidal functions typically protect the host against periodontitis. However, a number of periodontal pathogens developed survival strategies to evade neutrophil microbicidal functions while promoting inflammation, which provides a source of nutrients for bacterial growth. Research on periodontal pathogens has largely focused on a few established species: Tannerella forsythia, Treponema denticola, Fusobacterium nucleatum, Aggregatibacter actinomycetemcomitans, and Porphyromonas gingivalis. However, advances in culture-independent techniques have facilitated the identification of new bacterial species in periodontal lesions, such as the two Gram-positive anaerobes, Filifactor alocis and Peptoanaerobacter stomatis, whose characterization of pathogenic potential has not been fully described. Additionally, there is not a full understanding of the pathogenic mechanisms used against neutrophils by organisms that are abundant in periodontal lesions. This presents a substantial barrier to the development of new approaches to prevent or ameliorate the disease. In this review, we first summarize the neutrophil functions affected by the established periodontal pathogens listed above, denoting unknown areas that still merit a closer look. Then, we review the literature on neutrophil functions and the emerging periodontal pathogens, F. alocis and P. stomatis, comparing the effects of the emerging microbes to that of established pathogens, and speculate on the contribution of these putative pathogens to the progression of periodontal disease.
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Affiliation(s)
- Irina Miralda
- Department of Oral Immunology and Infectious Diseases, School of Dentistry, University of Louisville, Louisville, KY, USA
| | - Silvia M Uriarte
- Department of Oral Immunology and Infectious Diseases, School of Dentistry, University of Louisville, Louisville, KY, USA
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Vitkov L, Minnich B, Knopf J, Schauer C, Hannig M, Herrmann M. NETs Are Double-Edged Swords with the Potential to Aggravate or Resolve Periodontal Inflammation. Cells 2020; 9:E2614. [PMID: 33291407 PMCID: PMC7762037 DOI: 10.3390/cells9122614] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 12/01/2020] [Accepted: 12/02/2020] [Indexed: 12/24/2022] Open
Abstract
Periodontitis is a general term for diseases characterised by inflammatory destruction of tooth-supporting tissues, gradual destruction of the marginal periodontal ligament and resorption of alveolar bone. Early-onset periodontitis is due to disturbed neutrophil extracellular trap (NET) formation and clearance. Indeed, mutations that inactivate the cysteine proteases cathepsin C result in the massive periodontal damage seen in patients with deficient NET formation. In contrast, exaggerated NET formation due to polymorphonuclear neutrophil (PMN) hyper-responsiveness drives the pathology of late-onset periodontitis by damaging and ulcerating the gingival epithelium and retarding epithelial healing. Despite the gingival regeneration, periodontitis progression ends with almost complete loss of the periodontal ligament and subsequent tooth loss. Thus, NETs help to maintain periodontal health, and their dysregulation, either insufficiency or surplus, causes heavy periodontal pathology and edentulism.
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Affiliation(s)
- Ljubomir Vitkov
- Department of Biosciences, Vascular & Exercise Biology Unit, University of Salzburg, 5020 Salzburg, Austria; (L.V.); (B.M.)
- Clinic of Operative Dentistry, Periodontology and Preventive Dentistry, Saarland University, 66424 Homburg, Germany
| | - Bernd Minnich
- Department of Biosciences, Vascular & Exercise Biology Unit, University of Salzburg, 5020 Salzburg, Austria; (L.V.); (B.M.)
| | - Jasmin Knopf
- Department of Internal Medicine 3—Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, 91054 Erlangen, Germany; (J.K.); (C.S.); (M.H.)
| | - Christine Schauer
- Department of Internal Medicine 3—Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, 91054 Erlangen, Germany; (J.K.); (C.S.); (M.H.)
| | - Matthias Hannig
- Clinic of Operative Dentistry, Periodontology and Preventive Dentistry, Saarland University, 66424 Homburg, Germany
| | - Martin Herrmann
- Department of Internal Medicine 3—Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, 91054 Erlangen, Germany; (J.K.); (C.S.); (M.H.)
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Li W, Zhang Z, Wang ZM. Differential immune cell infiltrations between healthy periodontal and chronic periodontitis tissues. BMC Oral Health 2020; 20:293. [PMID: 33109155 PMCID: PMC7590666 DOI: 10.1186/s12903-020-01287-0] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 10/18/2020] [Indexed: 12/16/2022] Open
Abstract
Background Host immunity plays an important role against oral microorganisms in periodontitis. Methods This study assessed the infiltrating immune cell subtypes in 133 healthy periodontal and 210 chronic periodontitis tissues from Gene Expression Omnibus (GEO) datasets using the CIBERSORT gene signature files. Results Plasma cells, naive B cells and neutrophils were all elevated in periodontitis tissues, when compared to those in healthy controls. In contrast, memory B cells, resting dendritic, mast cells and CD4 memory cells, as well as activated mast cells, M1 and M2 macrophages, and follicular helper T cells, were mainly present in healthy periodontal tissues. Furthermore, these periodontitis tissues generally contained a higher proportion of activated CD4 memory T cells, while the other subtypes of T cells, including resting CD4 memory T cells, CD8 T cells, follicular helper T cells (TFH) and regulatory T cells (Tregs), were relatively lower in periodontitis tissues, when compared to healthy tissues. The ratio of dendritic and mast cells and macrophages was lower in periodontitis tissues, when compared to healthy tissues. In addition, there was a significant negative association of plasma cells with most of the other immune cells, such as plasma cells vs. memory B cells (γ = − 0.84), plasma cells vs. resting dendritic cells (γ = − 0.64), plasma cells vs. resting CD4 memory T cells (γ = 0.50), plasma cells versus activated dendritic cells (γ = − 0.46), plasma cells versus TFH (γ = − 0.46), plasma cells versus macrophage M2 cells (γ = − 0.43), or plasma cells versus macrophage M1 cells (γ = − 0.40), between healthy control and periodontitis tissues. Conclusion Plasma cells, naive B cells and neutrophils were all elevated in periodontitis tissues. The infiltration of different immune cell subtypes in the periodontitis site could lead the host immunity against periodontitis.
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Affiliation(s)
- Wei Li
- Department of Stomatology, Beijing Chao-Yang Hospital, Capital Medical University, 8th Gongti South Road, Beijing, 100020, China
| | - Zheng Zhang
- Department of Periodontology, Tianjin Stomatological Hospital, Tianjin Key Laboratory of Oral Function Reconstruction, Hospital of Stomatology, Nankai University, 75th Dagu North Road, Tianjin, 300000, China.
| | - Zuo-Min Wang
- Department of Stomatology, Beijing Chao-Yang Hospital, Capital Medical University, 8th Gongti South Road, Beijing, 100020, China.
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