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1.
J Leukoc Biol ; 110(3): 511-524, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34342041

RESUMO

Periodontitis is one of the most common oral diseases worldwide, and it is associated with various systemic diseases, including cognitive diseases. STAT3 regulates the inflammatory cascade and influences adaptive immunity by modulating Th17/Treg cell differentiation. In this study, we aimed to explore the effect of adaptive immunity inside and outside the brain on the association between periodontitis and cognitive impairment and understand the role of the STAT3 signaling pathway. We established Porphyromonas gingivalis LPS-induced periodontitis mice models by injecting P. gingivalis LPS into the gingival sulcus of mice. Behavioral tests showed that learning and memory abilities were impaired. The flow cytometry data showed an imbalance in the Th17/Treg ratio in the blood and brain samples of the mice. The expression of Th17-related cytokines (IL-1ß, IL-17A, IL-21, and IL-22) increased, whereas that of Treg-related cytokines (IL-2 and IL-10) decreased in both the blood and the brain. The level of LPS increased and the STAT3 signaling pathway was activated during this process. These effects were reversed by C188-9, a STAT3 inhibitor. In conclusion, P. gingivalis LPS-induced periodontitis may promote the occurrence and progression of cognitive impairment by modulating the Th17/Treg balance inside and outside the brain. The STAT3 signaling pathway may have immunoregulatory effects on the mouth-to-brain axis.


Assuntos
Disfunção Cognitiva/imunologia , Disfunção Cognitiva/microbiologia , Periodontite/imunologia , Periodontite/microbiologia , Porphyromonas gingivalis/fisiologia , Fator de Transcrição STAT3/metabolismo , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Processo Alveolar/patologia , Animais , Astrócitos/patologia , Reabsorção Óssea/complicações , Reabsorção Óssea/imunologia , Reabsorção Óssea/microbiologia , Reabsorção Óssea/patologia , Disfunção Cognitiva/complicações , Disfunção Cognitiva/diagnóstico por imagem , Citocinas/metabolismo , Gengiva/patologia , Lipopolissacarídeos , Memória , Camundongos , Microglia/patologia , Periodontite/complicações , Periodontite/diagnóstico por imagem , Transdução de Sinais , Aprendizagem Espacial
2.
Int J Mol Sci ; 22(11)2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-34070915

RESUMO

Systemic inflammation induced by periodontitis is suggested to be the link between periodontitis and cardiovascular disease. The aim of this work was to explore the oral microbiome in periodontitis in relation to disease severity and systemic inflammation. The saliva and subgingival microbiome from periodontal pocket samples of patients with severe (n = 12) and mild periodontitis (n = 13) were analyzed using metagenomic shotgun sequencing. The taxa and pathways abundances were quantified. The diversity was assessed and the abundances to phenotype associations were performed using ANCOM and linear regression. A panel of inflammatory markers was measured in blood and was associated with taxa abundance. The microbial diversity and species richness did not differ between severe and mild periodontitis in either saliva or periodontal pockets. However, there were significant differences in the microbial composition between severe and mild periodontitis in the subgingival microbiome (i.e., pocket samples) and, in a lower grade, in saliva, and this is positively associated with systemic inflammatory markers. The "red complex" and "cluster B" abundances in periodontal pockets were strongly associated with inflammatory markers interleukin-6 and the white blood cell count. Our data suggest that systemic inflammation in severe periodontitis may be driven by the oral microbiome and may support the indirect (inflammatory) mechanism for the association between periodontitis and cardiovascular disease.


Assuntos
Metagenoma , Microbiota/genética , Periodontite/microbiologia , Periodonto/microbiologia , Idoso , Biomarcadores/metabolismo , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/microbiologia , Doenças Cardiovasculares/patologia , Feminino , Expressão Gênica , Variação Genética , Humanos , Inflamação , Proteína Antagonista do Receptor de Interleucina 1/genética , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Leucócitos/imunologia , Leucócitos/microbiologia , Masculino , Pessoa de Meia-Idade , Periodontite/complicações , Periodontite/imunologia , Periodontite/patologia , Periodonto/imunologia , Periodonto/patologia , Fenótipo , Filogenia , Índice de Gravidade de Doença
3.
Front Immunol ; 12: 667862, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34177907

RESUMO

With the pandemic of COVID-19, maintenance of oral health has increasingly become the main challenge of global health. Various common oral diseases, such as periodontitis and oral cancer, are closely associated with immune disorders in the oral mucosa. Regulatory T cells (Treg) are essential for maintaining self-tolerance and immunosuppression. During the process of periodontitis and apical periodontitis, two typical chronic immune-inflammatory diseases, Treg contributes to maintain host immune homeostasis and minimize tissue damage. In contrast, in the development of oral precancerous lesions and oral cancer, Treg is expected to be depleted or down-regulated to enhance the anti-tumor immune response. Therefore, a deeper understanding of the distribution, function, and regulatory mechanisms of Treg cells may provide a prospect for the immunotherapy of oral diseases. In this review, we summarize the distribution and multiple roles of Treg in different oral diseases and discuss the possible mechanisms involved in Treg cell regulation, hope to provide a reference for future Treg-targeted immunotherapy in the treatment of oral diseases.


Assuntos
COVID-19/imunologia , Imunoterapia/métodos , Neoplasias Bucais/imunologia , Periodontite/imunologia , SARS-CoV-2/fisiologia , Linfócitos T Reguladores/imunologia , Animais , Humanos , Tolerância Imunológica , Tolerância a Antígenos Próprios
4.
J Immunol ; 206(10): 2386-2392, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33952619

RESUMO

Periodontal disease (PD) is a chronic destructive inflammatory disease of the tooth-supporting structures that leads to tooth loss at its advanced stages. Although the disease is initiated by a complex organization of oral microorganisms in the form of a plaque biofilm, it is the uncontrolled immune response to periodontal pathogens that fuels periodontal tissue destruction. IL-17A has been identified as a key cytokine in the pathogenesis of PD. Despite its well documented role in host defense against invading pathogens at oral barrier sites, IL-17A-mediated signaling can also lead to a detrimental inflammatory response, causing periodontal bone destruction. In this study, we developed a local sustained delivery system that restrains IL-17A hyperactivity in periodontal tissues by incorporating neutralizing anti-IL-17A Abs in poly(lactic-coglycolic) acid microparticles (MP). This formulation allowed for controlled release of anti-IL-17A in the periodontium of mice with ligature-induced PD. Local delivery of anti-IL-17A MP after murine PD induction inhibited alveolar bone loss and osteoclastic activity. The anti-IL-17A MP formulation also decreased expression of IL-6, an IL-17A target gene known to induce bone resorption in periodontal tissues. This study demonstrates proof of concept that local and sustained release of IL-17A Abs constitutes a promising therapeutic strategy for PD and may be applicable to other osteolytic bone diseases mediated by IL-17A-driven inflammation.


Assuntos
Perda do Osso Alveolar/tratamento farmacológico , Perda do Osso Alveolar/imunologia , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Neutralizantes/imunologia , Sistemas de Liberação de Medicamentos/métodos , Interleucina-17/imunologia , Periodontite/tratamento farmacológico , Periodontite/imunologia , Animais , Cápsulas , Modelos Animais de Doenças , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Osteólise/tratamento farmacológico , Osteólise/imunologia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Resultado do Tratamento
5.
J Leukoc Biol ; 110(3): 461-473, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34057740

RESUMO

Periodontitis induced by bacteria especially Porphyromonas gingivalis (P. gingivalis) is the most prevalent microbial disease worldwide and is a significant risk factor for systemic diseases such as rheumatoid arthritis (RA). RA and periodontitis share similar clinical and pathologic features. Moreover, the prevalence of RA is much higher in patients with periodontitis than in those without periodontitis. To explore the immunologic mechanism of periodontitis involved in RA, we established a mouse model of periodontitis and then induced RA. According to the results of paw thickness, arthritis clinical score, arthritis incidence, microscopic lesion using H&E staining, and micro-CT analysis, periodontitis induced by P. gingivalis promoted the occurrence and development of collagen-induced arthritis (CIA) in mice. Furthermore, periodontitis enhanced the frequency of CD19+ B cells, Th17, Treg, gMDSCs, and mMDSCs, whereas down-regulated IL-10 producing regulatory B cells (B10) in CIA mice preinduced for periodontitis with P. gingivalis. In vitro stimulation with splenic cells revealed that P. gingivalis directly enhanced differentiation of Th17, Treg, and mMDSCs but inhibited the process of B cell differentiation into B10 cells. Considering that adoptive transfer of B10 cells prevent RA development, our study, although preliminary, suggests that down-regulation of B10 cells may be the key mechanism that periodontitis promotes RA as the other main immune suppressive cells such as Treg and MDSCs are up-regulated other than down-regulated in group of P. gingivalis plus CIA.


Assuntos
Artrite Reumatoide/imunologia , Artrite Reumatoide/microbiologia , Periodontite/microbiologia , Porphyromonas gingivalis/patogenicidade , Animais , Antígenos CD19/metabolismo , Artrite Experimental/imunologia , Artrite Experimental/microbiologia , Artrite Reumatoide/diagnóstico por imagem , Modelos Animais de Doenças , Regulação para Baixo , Inflamação/patologia , Camundongos , Células Supressoras Mieloides/metabolismo , Periodontite/diagnóstico por imagem , Periodontite/imunologia , Porphyromonas gingivalis/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia
6.
J Leukoc Biol ; 110(3): 565-576, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34043832

RESUMO

Periodontitis is characterized by the periodontium's pathologic destruction due to the host's overwhelmed inflammation to the dental plaque. The bacterial infections and subsequent host immune responses have shaped a distinct microenvironment, which generally affects resident periodontal ligament stem cells (PDLSCs). Interestingly, recent studies have revealed that impaired PDLSCs may also contribute to the disturbance of periodontal homeostasis. The putative vicious circle underlying the interesting "positive feedback" of PDLSCs in the periodontitis niche remains a hot research topic, whereas the inseparable interactions between resident PDLSCs and the periodontitis niche are still not fully understood. This review provides a microscopic view on the periodontitis progression, especially the quick but delicate immune responses to oral dysbacterial infections. We also summarize the interesting crosstalk of the resident PDLSCs with their surrounding periodontitis niche and potential mechanisms. Particularly, the microenvironment reduces the osteogenic properties of resident PDLSCs, which are closely related to their reparative activity. Reciprocally, these impaired PDLSCs may disrupt the microenvironment by aggravating the host immune responses, promoting aberrant angiogenesis, and facilitating the osteoclastic activity. We further recommend that more in-depth studies are required to elucidate the interactions of PDLSCs with the periodontal microenvironment and provide novel interventions for periodontitis.


Assuntos
Comunicação Celular , Ligamento Periodontal/patologia , Periodontite/patologia , Células-Tronco/patologia , Humanos , Imunidade , Modelos Biológicos , Periodontite/imunologia
7.
Nutrients ; 13(4)2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33916342

RESUMO

Inflammation-modulating elements are recognized periodontitis (PD) risk factors, nevertheless, the association between dietary inflammatory index (DII) and PD has never been appraised. We aimed to assess the association between DII and PD and the mediation effect of DII in the association of PD with systemic inflammation. Using the National Health and Nutrition Examination Survey 2009-2010, 2011-2012 and 2013-2014, participants who received periodontal exam and provided dietary recall data were included. The inflammatory potential of diet was calculated via DII. PD was defined according to the 2012 case definition. White blood cells (WBC), segmented neutrophils and C-reactive protein (CRP) were used as proxies for systemic inflammation. The periodontal measures were regressed across DII values using adjusted multivariate linear regression and adjusted mediation analysis. Overall, 10,178 participants were included. DII was significantly correlated with mean periodontal probing depth (PPD), mean clinical attachment loss (CAL), thresholds of PPD and CAL, WBC, segmented neutrophils and DII (p < 0.01). A linear regression logistic adjusted for multiple confounding variables confirmed the association between DII and mean PPD (B = 0.02, Standard Error [SE]: 0.02, p < 0.001) and CAL (B = -0.02, SE: 0.01, p < 0.001). The association of mean PPD and mean CAL with both WBC and segmented neutrophils were mediated by DII (from 2.1 to 3.5%, p < 0.001). In the 2009-2010 subset, the association of mean CAL with serum CRP was mediated by DII (52.0%, p < 0.01). Inflammatory diet and PD may be associated. Also, the inflammatory diet significantly mediated the association of leukocyte counts and systemic inflammation with PD.


Assuntos
Proteína C-Reativa/análise , Comportamento Alimentar/fisiologia , Leucócitos/imunologia , Periodontite/epidemiologia , Adulto , Idoso , Estudos Transversais , Feminino , Humanos , Inflamação/sangue , Inflamação/diagnóstico , Inflamação/imunologia , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Inquéritos Nutricionais/estatística & dados numéricos , Índice Periodontal , Periodontite/diagnóstico , Periodontite/imunologia , Prevalência , Medição de Risco/métodos , Fatores de Risco , Estados Unidos/epidemiologia
8.
Int J Mol Sci ; 22(9)2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-33925019

RESUMO

Periodontitis is considered a promoter of many systemic diseases, but the signaling pathways of this interconnection remain elusive. Recently, it became evident that certain microbial challenges promote a heightened response of myeloid cell populations to subsequent infections either with the same or other pathogens. This phenomenon involves changes in the cell epigenetic and transcription, and is referred to as ''trained immunity''. It acts via modulation of hematopoietic stem and progenitor cells (HSPCs). A main modulation driver is the sustained, persistent low-level transmission of lipopolysaccharide from the periodontal pocket into the peripheral blood. Subsequently, the neutrophil phenotype changes and neutrophils become hyper-responsive and prone to boosted formation of neutrophil extracellular traps (NET). Cytotoxic neutrophil proteases and histones are responsible for ulcer formations on the pocket epithelium, which foster bacteremia and endoxemia. The latter promote systemic low-grade inflammation (SLGI), a precondition for many systemic diseases and some of them, e.g., atherosclerosis, diabetes etc., can be triggered by SLGI alone. Either reverting the polarized neutrophils back to the homeostatic state or attenuation of neutrophil hyper-responsiveness in periodontitis might be an approach to diminish or even to prevent systemic diseases.


Assuntos
Doença/etiologia , Endotoxemia/imunologia , Neutrófilos/fisiologia , Periodontite/complicações , Animais , Endotoxemia/metabolismo , Humanos , Lipopolissacarídeos/metabolismo , Periodontite/imunologia , Periodontite/metabolismo
9.
Int J Mol Sci ; 22(7)2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33807391

RESUMO

Salivary levels of interleukin-8 (IL-8) are elevated in patients with periodontitis. Caffeic acid phenethyl ester (CAPE) improves the periodontal status in subjects. However, whether CAPE can reduce IL-8 expression is unclear. We collected saliva to determine proinflammatory cytokine levels and used subgingival calculus and surrounding tissues from patients with periodontitis for oral microbiota analysis via 16s ribosomal RNA gene sequencing. THP-1 cells were stimulated with sterile-filtered saliva from patients, and target gene/protein expression was assessed. IL-8 mRNA expression was analyzed in saliva-stimulated THP-1 cells treated with CAPE and the heme oxygenase-1 (HO-1) inhibitor tin-protoporphyrin (SnPP). In 72 symptomatic individuals, IL-8 was correlated with periodontal inflammation (bleeding on probing, r = 0.45; p < 0.001) and disease severity (bleeding on probing, r = 0.45; p < 0.001) but not with the four oral microbiota species tested. Reduced salivary IL-8 secretion was correlated with effective periodontitis treatment (r = 0.37, p = 0.0013). In THP-1 cells, saliva treatment induced high IL-8 expression and IKK2 and nuclear factor-κB (NF-κB) phosphorylation. However, the IKK inhibitor BMS-345541, NF-κB inhibitor BAY 11-7082, and CAPE attenuated saliva-induced IL-8 expression. CAPE induced HO-1 expression and inhibited IKK2, IκBα, and NF-κB phosphorylation. Blocking HO-1 decreased the anti-inflammatory activity of CAPE. The targeted suppression of IL-8 production using CAPE reduces inflammation and periodontitis.


Assuntos
Ácidos Cafeicos/farmacologia , Interleucina-8/metabolismo , Periodontite/tratamento farmacológico , Álcool Feniletílico/análogos & derivados , Anti-Inflamatórios/farmacologia , Ácidos Cafeicos/metabolismo , Citocinas/metabolismo , Heme Oxigenase-1/metabolismo , Humanos , Proteínas I-kappa B/metabolismo , Inflamação/tratamento farmacológico , Interleucina-8/antagonistas & inibidores , Lipopolissacarídeos/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , Periodontite/imunologia , Periodontite/metabolismo , Álcool Feniletílico/metabolismo , Álcool Feniletílico/farmacologia , Fosforilação/efeitos dos fármacos , Saliva/química , Células THP-1
10.
J Cell Mol Med ; 25(7): 3634-3645, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33724691

RESUMO

The role of epigenetic regulation in immunity is emerging, especially for RNA N6-methyladenosine (m6A) modification. However, little is known about the role of m6A in the regulation of the immune microenvironment of periodontitis. Thus, we aim to investigate the impact of m6A modification in periodontitis immune microenvironment. The RNA modification patterns mediated by 23 m6A-regulators were systematically evaluated in 310 periodontitis samples. The impact of m6A modification on immune microenvironment characteristics was explored, including infiltrating immunocytes, immune reaction gene-sets and HLAs (human leukocyte antigen) gene. m6A phenotype-related immune genes were also identified. 17 m6A regulators were dysregulated and a 15-m6A regulator signature can well distinguish periodontitis and control samples. ALKBH5 and FMR1 are closely related to infiltrating monocyte abundance. ELAVL1 and CBLL1 are significant regulators in immune reaction of TNF_Family_Members_Receptors and Cytokine. The expression of HLA-B and HLA-DOA is affected by ALKBH5 and LRPPRC. 3 distinct RNA modification patterns mediated by 23 m6A regulators were identified. They differ from immunocyte abundance, immune reaction and HLA gene. 1631 m6A phenotype-related genes and 70 m6A-mediated immune genes were identified, and the biological functions of these were explored. Our finding demonstrated the m6A modification plays a crucial role in the diversity and complexity of the immune microenvironment of periodontitis.


Assuntos
Adenosina/análogos & derivados , Microambiente Celular , Metilação , Periodontite/genética , Periodontite/imunologia , Processamento Pós-Transcricional do RNA , RNA/metabolismo , Adenosina/química , Adenosina/fisiologia , Homólogo AlkB 5 da RNA Desmetilase/metabolismo , Proteína Semelhante a ELAV 1/metabolismo , Epigênese Genética , Proteína do X Frágil de Retardo Mental/metabolismo , Regulação da Expressão Gênica , Humanos , Proteínas de Neoplasias/metabolismo , Periodontite/metabolismo , Mapas de Interação de Proteínas , Ubiquitina-Proteína Ligases/metabolismo
11.
Front Immunol ; 12: 641562, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33679805

RESUMO

Natural killer-like B (NKB) cells, which are newly identified immune subsets, reveal a critical immunoregulatory property in the eradication of microbial infection via the secretion of interleukin (IL)-18. For the first time, this study investigated the role of NKB cells in secreting IL-18 in the pathogenesis of periodontitis. In this study, NKB cells' percentage and IL-18 concentration in peripheral blood and periodontium in periodontitis patients was measured using flow cytometry and ELISA. The role of IL-18 in regulating periodontal inflammation was examined in a Porphyromonas gingivalis (P. gingivalis)-induced periodontitis murine model. Peripheral and periodontal-infiltrating CD3-CD19+NKp46+ NKB cells, which were the main source of IL-18, were elevated and correlated with attachment loss in periodontitis patients. In vitro IL-18 stimulation promoted proinflammatory cytokine production in periodontal ligament cells. P. gingivalis infection induced elevation of IL-18 receptor in periodontium in a periodontitis murine model. IL-18 neutralization not only suppressed P. gingivalis-induced alveolar bone resorption, but also inhibited recruitment of antigen-non-specific inflammatory cells into the periodontium, probably via dampening expressions of cytokines, chemokines, and matrix metalloproteinases. NKB cells secreting IL-18 appeared to be an important mediator in the inflammatory response following intraoral P. gingivalis infection. These findings might be relevant to the development of immunotherapies for periodontitis.


Assuntos
Subpopulações de Linfócitos B/imunologia , Interleucina-18/imunologia , Periodontite/imunologia , Adulto , Animais , Infecções por Bacteroidaceae/imunologia , Feminino , Humanos , Inflamação/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Porphyromonas gingivalis
12.
Int Immunopharmacol ; 95: 107505, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33725636

RESUMO

The purpose of the present study was to investigate the pharmacological effect of Fisetin on experimental periodontitis in rats and explore its potential mechanism. The ligature/LPS method was used to induce periodontitis in rats. LPS was employed to cause inflammation in Human gingival fibroblasts (HGF). The transfections with FGFR1 SiRNA, NLRP3 SiRNA and the selective TLR4 inhibitor TAK242 were used to investigate the mechanism of Fisetin-mediated inflammatory reaction in LPS-induced HGF. As a result, Fisetin reduced the alveolar bone gap, reversed histopathological lesion and inhibited serum inflammatory cytokine concentration in periodontitis rats. Fisetin decreased the inflammatory cytokine contents in the supernatant of LPS-induced HGF. The inhibitory effect of Fisetin might be attributed to FGFR1/TLR4/NLRP3 inflammasome pathway both in vivo and in vitro. The suppressions of FGFR1, TLR4 and NLRP3 proved that FGFR1/TLR4/NLRP3 signaling was involved in the Fisetin-mediated inflammatory response. Fisetin also inhibited NLRP3 priming. The data demonstrated that Fisetin attenuated periodontitis by inhibiting inflammatory reaction via FGFR1/TLR4/NLRP3 inflammasome pathway.


Assuntos
Anti-Inflamatórios/uso terapêutico , Flavonóis/uso terapêutico , Inflamassomos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Periodontite/tratamento farmacológico , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/imunologia , Receptor 4 Toll-Like/imunologia , Animais , Anti-Inflamatórios/farmacologia , Linhagem Celular , Fibroblastos/efeitos dos fármacos , Flavonóis/farmacologia , Gengiva/citologia , Humanos , Lipopolissacarídeos , Masculino , Periodontite/imunologia , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
13.
J Int Med Res ; 49(3): 3000605211002695, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33745336

RESUMO

Over the past several decades, studies have demonstrated the existence of bi-directional relationships between periodontal disease and systemic conditions. Periodontitis is a polymicrobial and multifactorial disease involving both host and environmental factors. Tissue destruction is primarily associated with hyperresponsiveness of the host resulting in release of inflammatory mediators. Pro-inflammatory cytokines play a major role in bacterial stimulation and tissue destruction. In addition, these cytokines are thought to underlie the associations between periodontitis and systemic conditions. Current research suggests that increased release of cytokines from host cells, referred to as the cytokine storm, is associated with disease progression in patients with coronavirus disease 2019 (COVID-19). An intersection between periodontitis and pulmonary disease is biologically plausible. Hence, we reviewed the evidence linking COVID-19, cytokines, and periodontal disease. Plaque control is essential to prevent exchange of bacteria between the mouth and the lungs, reducing the risk of lung disease. Understanding these associations may help identify individuals at high risk and deliver appropriate care at early stages.


Assuntos
COVID-19/imunologia , Síndrome da Liberação de Citocina/imunologia , Placa Dentária/imunologia , Interações Hospedeiro-Patógeno/imunologia , Periodontite/imunologia , SARS-CoV-2/patogenicidade , Estresse Psicológico/imunologia , COVID-19/complicações , COVID-19/genética , COVID-19/virologia , Síndrome da Liberação de Citocina/complicações , Síndrome da Liberação de Citocina/genética , Síndrome da Liberação de Citocina/virologia , Placa Dentária/complicações , Placa Dentária/genética , Placa Dentária/virologia , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Padrões Moleculares Associados a Patógenos/imunologia , Padrões Moleculares Associados a Patógenos/metabolismo , Periodontite/complicações , Periodontite/genética , Periodontite/virologia , SARS-CoV-2/imunologia , Transdução de Sinais , Estresse Psicológico/complicações , Estresse Psicológico/genética , Estresse Psicológico/virologia , Dente/imunologia , Dente/patologia , Dente/virologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
14.
Int J Med Sci ; 18(2): 432-440, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33390812

RESUMO

Prevotella nigrescens is an oral pathogen that is frequently observed in the subgingival plaque of periodontitis patients. Interleukin-1ß (IL-1ß) is known to be involved in the immunopathology of periodontal diseases and has been implicated in the destruction of bone. In this study, we investigated the mechanism of IL-1ß production by P. nigrescens in murine bone marrow-derived dendritic cells (BMDCs). Our results showed that a host receptor, Toll-like receptor 2 (TLR2), but not TLR4 is required for pro-IL-1ß induction and nucleotide-binding oligomerization domain like receptor pyrin domain containing 3 (NLRP3) priming in BMDCs in response to P. nigrescens and activation of the NLRP3 inflammasome is necessary for processing of pro-IL-1ß into mature IL-1ß. In addition, an inhibitor assay revealed that production of reactive oxygen species, P2X7R activity, and release of cathepsin B are involved in IL-1ß production in BMDCs in response to P. nigrescens.


Assuntos
Infecções por Bactérias Gram-Negativas/imunologia , Interleucina-1beta/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Periodontite/imunologia , Prevotella nigrescens/imunologia , Receptor 2 Toll-Like/metabolismo , Animais , Catepsina B/metabolismo , Células Cultivadas , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Infecções por Bactérias Gram-Negativas/microbiologia , Humanos , Inflamassomos/imunologia , Inflamassomos/metabolismo , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Periodontite/microbiologia , Cultura Primária de Células , Espécies Reativas de Oxigênio/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Receptor 2 Toll-Like/genética
15.
BMC Complement Med Ther ; 21(1): 43, 2021 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-33485352

RESUMO

BACKGROUND: Periodontitis is a chronic infection initiated by oral bacterial and their virulence factors, yet the severity of periodontitis is largely determined by the dysregulated host immuno-inflammatory response. Baicalein is a flavonoid extracted from Scutellaria baicalensis with promising anti-inflammatory properties. This study aims to clarify the anti-inflammatory and osteogenic effects of baicalein in periodontal ligament cells (PDLCs) treated with lipopolysaccharides (LPS). METHODS: Human PDLCs were incubated with baicalein (0-100 µM) for 2 h prior to LPS challenge for 24 h. MTT analysis was adopted to assess the cytoxicity of baicalein. The mRNA and protein expression of inflammatory and osteogenic markers were measured by real-time polymerase chain reaction (PCR), western blot and enzyme-linked immunosorbent assay (ELISA) as appropriate. Alkaline phosphatase (ALP) and Alizarin red S (ARS) staining were performed to evaluate the osteogenic differentiation of PDLCs. The expression of Wnt/ß-catenin and mitogen-activated protein kinase (MAPK) signaling related proteins was assessed by western blot. RESULTS: MTT results showed that baicalein up to 100 µM had no cytotoxicity on PDLCs. Baicalein significantly attenuated the inflammatory factors induced by LPS, including interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), matrix metalloprotein-1 (MMP-1), MMP-2 and monocyte chemoattractant protein 1 (MCP-1) at both mRNA and protein level. Moreover, MAPK signaling (ERK, JNK and p38) was significantly inhibited by baicalein, which may account for the mitigated inflammatory response. Next, we found that baicalein effectively restored the osteogenic differentiation of LPS-treated PDLCs, as shown by the increased ALP and ARS staining. Accordingly, the protein and gene expression of osteogenic markers, namely runt-related transcription factor 2 (RUNX2), collagen-I, and osterix were markedly upregulated. Importantly, baicalein could function as the Wnt/ß-catenin signaling activator, which may lead to the increased osteoblastic differentiation of PDLCs. CONCLUSIONS: With the limitation of the study, we provide in vitro evidence that baicalein ameliorates inflammatory response and restores osteogenesis in PDLCs challenged with LPS, indicating its potential use as the host response modulator for the management of periodontitis.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Flavanonas/farmacologia , Osteogênese/efeitos dos fármacos , Ligamento Periodontal/efeitos dos fármacos , Periodontite/tratamento farmacológico , Scutellaria baicalensis/química , Fosfatase Alcalina/genética , Fosfatase Alcalina/imunologia , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Quimiocina CCL2/genética , Quimiocina CCL2/imunologia , Humanos , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Lipopolissacarídeos/efeitos adversos , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/imunologia , Ligamento Periodontal/citologia , Ligamento Periodontal/imunologia , Periodontite/genética , Periodontite/imunologia , Periodontite/fisiopatologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/genética , beta Catenina/imunologia
16.
Exp Cell Res ; 400(2): 112505, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33516666

RESUMO

Inflammation and alveolar bone destruction constitute the main pathological process of periodontitis. However, the molecular mechanisms of bone destruction under the inflammation environment remain unclear. This study aims to explore the role of Ephrin-B2/EphB4 signaling in osteogenic differentiation under the inflammation environment. Mouse pre-osteoblasts MC3T3-E1 were pretreated with lipopolysaccharide of Porphyromonas gingivalis (Pg-LPS). The Ephrin-B2/EphB4 signaling was activated, and the osteogenic differentiation of cells was examined. The results showed that activation of Ephrin-B2/EphB4 signaling promoted the expression levels of osteogenic differentiation-related genes, and also relieved the inhibitory effect of Pg-LPS on osteogenesis. Noticeably, the effect of Ephrin-B2/EphB4 signaling might be related to the mitogen-activated protein kinase (MAPK) pathway. While applying Ephrin-B2-Fc and EphB4-Fc to periodontitis mice, we observed the reduction of alveolar crest destruction. The current study revealed the possible role of Ephrin-B2/EphB4 signaling in reducing bone destruction in periodontitis and suggested its potential values for further research.


Assuntos
Efrina-B2/metabolismo , Fragmentos Fc das Imunoglobulinas/imunologia , Inflamação/prevenção & controle , Osteoblastos/citologia , Osteogênese , Periodontite/prevenção & controle , Receptor EphB4/metabolismo , Animais , Diferenciação Celular , Efrina-B2/genética , Efrina-B2/imunologia , Inflamação/imunologia , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Osteoblastos/imunologia , Osteoblastos/metabolismo , Periodontite/imunologia , Periodontite/metabolismo , Receptor EphB4/genética , Receptor EphB4/imunologia , Transdução de Sinais
17.
Nat Rev Immunol ; 21(7): 426-440, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33510490

RESUMO

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.


Assuntos
Inflamação/epidemiologia , Doenças Periodontais/epidemiologia , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/imunologia , Doença de Alzheimer/microbiologia , Animais , Medula Óssea/imunologia , Causalidade , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/microbiologia , Comorbidade , Microbioma Gastrointestinal/imunologia , Humanos , Inflamação/imunologia , Doenças Inflamatórias Intestinais/epidemiologia , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/microbiologia , Modelos Biológicos , Boca/microbiologia , Doenças Periodontais/imunologia , Doenças Periodontais/microbiologia , Periodontite/epidemiologia , Periodontite/imunologia , Periodontite/microbiologia , Fatores de Risco
18.
J Alzheimers Dis ; 79(4): 1785-1800, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33459718

RESUMO

BACKGROUND: Although periodontitis is reportedly associated with increased cognitive decline in Alzheimer's disease, the mechanisms underlying this process remain unknown. Porphyromonas gingivalis lipopolysaccharide (P.g-LPS) is an endotoxin associated with periodontal disease. OBJECTIVE: We investigated the effect of periodontitis on learning capacity and memory of amyloid-ß protein precursor (AßPP)/presenilin (PS1) transgenic mice along with the mechanisms underlying these effects. METHODS: Mice were randomly assigned to three groups, namely AßPP/PS1 (control), P.g-LPS Injection, and P.g-LPS Injection + Ligation. Mice from the P.g-LPS Injection group were injected with P.g-LPS in the periodontal tissue three times per week for 8 weeks, while mice from the P.g-LPS Injection + Ligation group were injected with P.g-LPS and subjected to ligation of the gingival sulcus of the maxillary second molar. RESULTS: Expression of gingival proinflammatory cytokines as well as alveolar bone resorption in P.g-LPS-injected and ligatured mice was increased compared to that in control mice. Mice in the P.g-LPS Injection + Ligation group exhibited cognitive impairment and a significant reduction in the number of neurons. Glial cell activation in the experimental groups with significantly increased amyloid-ß (Aß) levels was more pronounced relative to the control group. Induction of periodontitis was concurrent with an increase in cyclooxygenase-2, inducible nitric oxide synthase, AßPP, and beta-secretase 1 expression and a decrease in A disintegrin and metalloproteinase domain-containing protein 10 expression. CONCLUSION: These findings indicated that periodontitis exacerbated learning and memory impairment in AßPP/PS1 mice and augmented Aß and neuroinflammatory responses. Our study provides a theoretical basis for risk prediction and early intervention of Alzheimer's disease and periodontitis.


Assuntos
Doença de Alzheimer/patologia , Cognição/fisiologia , Neuroglia/patologia , Neurônios/patologia , Periodontite/complicações , Doença de Alzheimer/imunologia , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Transgênicos , Neuroimunomodulação/fisiologia , Periodontite/imunologia
19.
Int J Mol Sci ; 22(3)2021 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-33513808

RESUMO

There is little known about the effect of the periodontopathogen Filifactor alocis on macrophages as key cells of the innate immune defense in the periodontium. Therefore, the aim of the present study was to investigate the effect of F. alocis and additionally of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNFα) on visfatin and other pro-inflammatory and proteolytic molecules associated with periodontitis in human macrophages. The presence of macrophage markers CD14, CD86, CD68, and CD163 was examined in gingival biopsies from healthy individuals and periodontitis patients. Human macrophages were incubated with F. alocis and TNFα for up to 2 d. The effects of both stimulants on macrophages were determined by real-time PCR, ELISA, immunocytochemistry, and immunofluorescence. F. alocis was able to significantly stimulate the synthesis of visfatin by human macrophages using TLR2 and MAPK pathways. In addition to visfatin, F. alocis was also able to increase the synthesis of cyclooxygenase 2, TNFα, and matrix metalloproteinase 1. Like F. alocis, TNFα was also able to stimulate the production of these proinflammatory and proteolytic molecules. Our results highlight the pathogenetic role of F. alocis in periodontal diseases and also underline the involvement of visfatin in the aetiopathogenesis of periodontitis.


Assuntos
Clostridiales/imunologia , Gengiva/metabolismo , Macrófagos/metabolismo , Nicotinamida Fosforribosiltransferase/biossíntese , Periodontite/imunologia , Receptor 2 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Antígenos CD/genética , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/genética , Antígenos de Diferenciação Mielomonocítica/metabolismo , Antígeno B7-2/genética , Antígeno B7-2/metabolismo , Ciclo-Oxigenase 2/biossíntese , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Gengiva/citologia , Gengiva/patologia , Humanos , Imuno-Histoquímica , Receptores de Lipopolissacarídeos/genética , Receptores de Lipopolissacarídeos/metabolismo , Sistema de Sinalização das MAP Quinases/imunologia , Macrófagos/efeitos dos fármacos , Metaloproteinase 1 da Matriz/biossíntese , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/metabolismo , Nicotinamida Fosforribosiltransferase/genética , Nicotinamida Fosforribosiltransferase/metabolismo , Periodontite/metabolismo , Periodontite/microbiologia , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
20.
Ann Rheum Dis ; 80(2): 162-168, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33004333

RESUMO

OBJECTIVES: An increased prevalence of periodontitis and perturbation of the oral microbiome has been identified in patients with rheumatoid arthritis (RA). The periodontal pathogen Porphyromonas gingivalis may cause local citrullination of proteins, potentially triggering anti-citrullinated protein antibody production. However, it is not known if oral dysbiosis precedes the onset of clinical arthritis. This study comprehensively characterised the oral microbiome in anti-cyclic citrullinated peptide (anti-CCP) positive at-risk individuals without clinical synovitis (CCP+at risk). METHODS: Subgingival plaque was collected from periodontally healthy and diseased sites in 48 CCP+at risk, 26 early RA and 32 asymptomatic healthy control (HC) individuals. DNA libraries were sequenced on the Illumina HiSeq 3000 platform. Taxonomic profile and functional capability of the subgingival microbiome were compared between groups. RESULTS: At periodontally healthy sites, CCP+at risk individuals had significantly lower microbial richness compared with HC and early RA groups (p=0.004 and 0.021). Microbial community alterations were found at phylum, genus and species levels. A large proportion of the community differed significantly in membership (523 species; 35.6%) and structure (575 species; 39.1%) comparing CCP+at risk and HC groups. Certain core species, including P. gingivalis, had higher relative abundance in the CCP+at risk group. Seventeen clusters of orthologous gene functional units were significantly over-represented in the CCP+at risk group compared with HC (adjusted p value <0.05). CONCLUSION: Anti-CCP positive at-risk individuals have dysbiotic subgingival microbiomes and increased abundance of P. gingivalis compared with controls. This supports the hypothesis that the oral microbiome and specifically P. gingivalis are important in RA initiation.


Assuntos
Artrite Reumatoide/microbiologia , Disbiose/imunologia , Microbiota/imunologia , Periodontite/microbiologia , Porphyromonas gingivalis/imunologia , Adulto , Anticorpos Anti-Proteína Citrulinada/sangue , Anticorpos Anti-Proteína Citrulinada/imunologia , Artrite Reumatoide/imunologia , Autoanticorpos/sangue , Autoanticorpos/imunologia , Disbiose/microbiologia , Feminino , Gengiva/imunologia , Gengiva/microbiologia , Humanos , Masculino , Pessoa de Meia-Idade , Periodontite/imunologia , Fatores de Risco
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