Epigenetic regulation of TLR2‐mediated periapical inflammation

Fernández, Alejandra; Veloso, Pablo; Astorga, Jessica; Rodrı́guez, Carmen; Torres, Vicente A.; Valdés, Macarena; Garrido, Mauricio; Gebicke‐Haerter, Peter J.; Hernández, Marcela

doi:10.1111/iej.13329

Cited by 12 publications

(19 citation statements)

References 34 publications

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“…Emerging evidence supports that DNA methylation can also act by regulating the binding of transcription factors (TF) or methyl-CpG-binding proteins in a CpG site-specific manner (52)(53)(54). Particularly in ALEOs, unmethylated CpG single-sites -10 and -12 are associated with transcriptional upregulation of TLR2 (10). Interestingly, these CpG single-sites are close to the NFkB binding sequence.…”

Section: Discussionmentioning

confidence: 99%

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CpG Single-Site Methylation Regulates TLR2 Expression in Proinflammatory PBMCs From Apical Periodontitis Individuals

et al. 2022

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IntroductionApical periodontitis (AP) is a common oral disease caused by the inflammatory destruction of the periapical tissues due to the infection of the root canal system of the tooth. It also contributes to systemic bacterial translocation, where peripheric mononuclear blood cells (PBMCs) can act as carriers. Toll-like receptor (TLR) 2 mediates the response to infection and activates inflammatory responses. DNA methylation can be induced by bacteria and contributes to the modulation of this response. Despite the evidence that supports the participation of PBMCs in immune-inflammatory disorders, the inflammatory profile and epigenetic regulatory mechanisms of PBMCs in AP individuals are unknown.AimTo determine TLR2 gene methylation and inflammatory profiles of PBMCs in AP.MethodsCross-sectional exploratory study. Otherwise, healthy individuals with AP (n=27) and controls (n=30) were included. PMBCs were isolated by a Ficoll gradient, cultured for 24 hours, and both RNA and DNA were extracted. DNA was bisulfite-treated, and specific sites at the promoter region of the TLR2 gene were amplified by qPCR using validated primers. To verify its amplification, agarose gels were performed. Then, the PCR product was sequenced. mRNA expression of TLR2 was determined by qPCR. The soluble levels of 105 inflammatory mediators were first explored with Proteome Profiler Human Cytokine Array Kit. Consequently, tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10, IL-6Rα, IL-1β, and IL-12p70 levels were measured by Multiplex assay.ResultsPBMCs from individuals with AP demonstrated a proinflammatory profile showing higher soluble levels of TNF-α, IL-6, and IL-1β compared to controls (p<0.05). Higher TLR2 expression and higher global methylation pattern of the promoter region of the gene were found in AP compared to controls (p<0.05). The CpGs single-sites at positions -166 and -146 were completely methylated, while the site -102 was totally unmethylated, independently of the presence of AP. DNA methylation of CpG single-sites in positions -77 and +24 was positively associated with TLR2 expression.ConclusionsPBMCs from AP subjects show a hyperinflammatory phenotype and TLR2 upregulation in association with single CpG-sites’ methylation from the TLR2 gene promoter, thereby contributing to a sustained systemic inflammatory load in individuals with periapical endodontic diseases.

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Section: Discussionmentioning

confidence: 99%

“…The interaction TLR2-ligand activates intercellular signaling that induces nuclear factor κ -B (NF κ B) translocation to the nucleus and the consequent inflammatory cascade activation ( 9 ). The expression of TLR2 can be regulated by transcriptional changes that depend on epigenetic modifications in ALEOs ( 10 ).…”

Section: Introductionmentioning

confidence: 99%

CpG Single-Site Methylation Regulates TLR2 Expression in Proinflammatory PBMCs From Apical Periodontitis Individuals

et al. 2022

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“…Our study group has previously demonstrated that the expression of toll-like receptors (TLR)-2 and -4, which are involved in the recognition of damage and pathogen molecular patterns, were positively correlated with VEGF-A in human ALEOs. In the same study, mRNA levels of VEGF-A were detected in both, asymptomatic and symptomatic AP [67]. The detection of VEGF-A in both clinical entities is related to its role in endothelial cell proliferation associated with chronic inflammation, apparently without participation in the clinical exacerbation of the disease.…”

Section: Apical Periodontitismentioning

confidence: 65%

“…The detection of VEGF-A in both clinical entities is related to its role in endothelial cell proliferation associated with chronic inflammation, apparently without participation in the clinical exacerbation of the disease. Instead, the symptoms might be mediated by other cytokines and angiogenic factors, like IL-6, TNF-α and CDH5, which were significantly higher in symptomatic compared to asymptomatic AP [67].…”

Section: Apical Periodontitismentioning

confidence: 92%

Vascular Endothelial Growth Factor: A Translational View in Oral Non-Communicable Diseases

et al. 2021

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Vascular endothelial growth factors (VEGFs) are vital regulators of angiogenesis that are expressed in response to soluble mediators, such as cytokines and growth factors. Their physiologic functions include blood vessel formation, regulation of vascular permeability, stem cell and monocyte/macrophage recruitment and maintenance of bone homeostasis and repair. In addition, angiogenesis plays a pivotal role in chronic pathologic conditions, such as tumorigenesis, inflammatory immune diseases and bone loss. According to their prevalence, morbidity and mortality, inflammatory diseases affecting periodontal tissues and oral cancer are relevant non-communicable diseases. Whereas oral squamous cell carcinoma (OSCC) is considered one of the most common cancers worldwide, destructive inflammatory periodontal diseases, on the other hand, are amongst the most prevalent chronic inflammatory conditions affecting humans and also represent the main cause of tooth loss in adults. In the recent years, while knowledge regarding the role of VEGF signaling in common oral diseases is expanding, new potential translational applications emerge. In the present narrative review we aim to explore the role of VEGF signaling in oral cancer and destructive periodontal inflammatory diseases, with emphasis in its translational applications as potential biomarkers and therapeutic targets.

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“…•Methylation is related to gene silencing (82). Hypomethylation of TLR2 promoter exacerbates periapical inflammatory and angiogenic responses in association with symptomatic apical periodontitis (83).…”

Section: Radicular Cystmentioning

confidence: 99%

Comparative Metabolomics Reveals the Microenvironment of Common T-Helper Cells and Differential Immune Cells Linked to Unique Periapical Lesions

et al. 2021

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Periapical abscesses, radicular cysts, and periapical granulomas are the most frequently identified pathological lesions in the alveolar bone. While little is known about the initiation and progression of these conditions, the metabolic environment and the related immunological behaviors were examined for the first time to model the development of each pathological condition. Metabolites were extracted from each lesion and profiled using gas chromatography-mass spectrometry in comparison with healthy pulp tissue. The metabolites were clustered and linked to their related immune cell fractions. Clusters I and J in the periapical abscess upregulated the expression of MMP-9, IL-8, CYP4F3, and VEGF, while clusters L and M were related to lipophagy and apoptosis in radicular cyst, and cluster P in periapical granuloma, which contains L-(+)-lactic acid and ethylene glycol, was related to granuloma formation. Oleic acid, 17-octadecynoic acid, 1-nonadecene, and L-(+)-lactic acid were significantly the highest unique metabolites in healthy pulp tissue, periapical abscess, radicular cyst, and periapical granuloma, respectively. The correlated enriched metabolic pathways were identified, and the related active genes were predicted. Glutamatergic synapse (16–20),-hydroxyeicosatetraenoic acids, lipophagy, and retinoid X receptor coupled with vitamin D receptor were the most significantly enriched pathways in healthy control, abscess, cyst, and granuloma, respectively. Compared with the healthy control, significant upregulation in the gene expression of CYP4F3, VEGF, IL-8, TLR2 (P < 0.0001), and MMP-9 (P < 0.001) was found in the abscesses. While IL-12A was significantly upregulated in cysts (P < 0.01), IL-17A represents the highest significantly upregulated gene in granulomas (P < 0.0001). From the predicted active genes, CIBERSORT suggested the presence of natural killer cells, dendritic cells, pro-inflammatory M1 macrophages, and anti-inflammatory M2 macrophages in different proportions. In addition, the single nucleotide polymorphisms related to IL-10, IL-12A, and IL-17D genes were shown to be associated with periapical lesions and other oral lesions. Collectively, the unique metabolism and related immune response shape up an environment that initiates and maintains the existence and progression of these oral lesions, suggesting an important role in diagnosis and effective targeted therapy.

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Epigenetic regulation of TLR2‐mediated periapical inflammation

Cited by 12 publications

References 34 publications

CpG Single-Site Methylation Regulates TLR2 Expression in Proinflammatory PBMCs From Apical Periodontitis Individuals

CpG Single-Site Methylation Regulates TLR2 Expression in Proinflammatory PBMCs From Apical Periodontitis Individuals

Vascular Endothelial Growth Factor: A Translational View in Oral Non-Communicable Diseases

Comparative Metabolomics Reveals the Microenvironment of Common T-Helper Cells and Differential Immune Cells Linked to Unique Periapical Lesions

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