Aberrant DNA methylation of the toll-like receptors 2 and 6 genes in patients with obstructive sleep apnea

Huang, Kuo Tung; Chen, Yung Che; Tseng, Chia Cheng; Huang, Chang; Su, Mao Chang; Wang, Ting Ya; Lin, Yong Yong; Zheng, Yi; Chang, Jen-Chieh; Chin, Chien Hung; Hsiao, Chang‐Chun; Lin, Meng C.

doi:10.1371/journal.pone.0228958

Cited by 9 publications

(7 citation statements)

References 42 publications

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“…DNA methylation, one of the main epigenetic modulating mechanisms, has been reported to regulate several chronic inflammatory pathologies ( 12 , 39 , 40 ). The CpG islands are highly susceptible to methylation reprogramming.…”

Section: Discussionmentioning

confidence: 99%

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%

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

et al. 2022

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“…Overexpression of Toll-Like Receptor (TLR) was observed in circulating monocytes of OSAS patients [ 47 ], and the TLR 6 gene is upregulated in peripheral blood cells through DNA methylation. In particular, the cytosine-phosphate-guanine (CPG) site number 1 is hypermethylated in patients with severe OSAS, and its methylation is reduced after at least 6 months of CPAP therapy [ 48 ]. Epigenetic studies also identified hypermethylation of interleukin 1 receptor 2 (IL1R2) and androgen receptors with increased expression of both [ 49 ].…”

Section: Resultsmentioning

confidence: 99%

“…Aldosterone is a molecule related to resistant hypertension, just as OSAS is a disease related to the same disorder [ 57 ]. The interaction between the increase in all the proinflammatory molecules and the endothelium could be one of the causes of the increased cardiovascular risk in OSAS, such as TNF, interleukins, NF-kB, TLR receptors, myeloid-related protein-8/14, the accumulation of pro-inflammatory metabolic M1-lie macrophages highly expressing CD36, fibrinogen, shock protein 70, monocyte chemotactic protein 1, highly sensitive C-reactive protein, P-selectin, soluble CD40, ICAM-1, VCAM-1, L-selectin, E-selectin and MPO [ 6 , 20 , 42 , 43 , 44 , 45 , 48 , 51 , 52 , 55 ].…”

Section: Discussionmentioning

confidence: 99%

Molecular Pathology, Oxidative Stress, and Biomarkers in Obstructive Sleep Apnea

Meliante

Zoccali

Cascone

et al. 2023

IJMS

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Obstructive sleep apnea syndrome (OSAS) is characterized by intermittent hypoxia (IH) during sleep due to recurrent upper airway obstruction. The derived oxidative stress (OS) leads to complications that do not only concern the sleep-wake rhythm but also systemic dysfunctions. The aim of this narrative literature review is to investigate molecular alterations, diagnostic markers, and potential medical therapies for OSAS. We analyzed the literature and synthesized the evidence collected. IH increases oxygen free radicals (ROS) and reduces antioxidant capacities. OS and metabolic alterations lead OSAS patients to undergo endothelial dysfunction, osteoporosis, systemic inflammation, increased cardiovascular risk, pulmonary remodeling, and neurological alterations. We treated molecular alterations known to date as useful for understanding the pathogenetic mechanisms and for their potential application as diagnostic markers. The most promising pharmacological therapies are those based on N-acetylcysteine (NAC), Vitamin C, Leptin, Dronabinol, or Atomoxetine + Oxybutynin, but all require further experimentation. CPAP remains the approved therapy capable of reversing most of the known molecular alterations; future drugs may be useful in treating the remaining dysfunctions.

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“…Therefore, interest focus on exploring biomarkers has been increasing for decades. In recent years, additional research on cellular immune has reported that macrophage polarization towards M1 subsets ( Khalyfa, Kheirandish-Gozal & Gozal, 2018 ), increased ratio of NLR ( Rha et al., 2020 ), PLR ( Kıvanc et al., 2018 ), CD8+T/CD4+T ( Domagała-Kulawik et al., 2015 ), and Th17/Treg ( Reale et al., 2020 ), as well as DNA methylation of toll-like receptor 2/6 ( Huang et al., 2020 ) in OSA patients, suggesting possible reactions to new endogenous antigens. Given the vital role of T cells in adaptive immunity, the question arises as to why and how T cell immunity is impaired in OSA.…”

Section: Discussionmentioning

confidence: 99%

T cell receptor repertoire as a novel indicator for identification and immune surveillance of patients with severe obstructive sleep apnea

Zhuo

et al. 2023

PeerJ

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Background Obstructive sleep apnea (OSA) is the most prevalent sleep disturbance that affects approximately 936 million people worldwide and leads to extensively increased incidence of cardiovascular disease, metabolic syndrome, neurological disorders, and traffic accidents. Severe OSA patients suffer a significantly higher risk of complications and worse comorbidity outcomes. Notwithstanding, with inadequate access to contact diagnosis based on polysomnography (PSG), numerous patients with severe sleep apnea have not been diagnosed, especially during the pandemic. Moreover, how the T cell immunity is impaired in OSA remains largely unknown. Methods We primarily investigated the T cell receptor (TCR) repertoires of 50 patients with severe OSA, 23 patients with mild-to-moderate OSA, 23 patients without OSA, and 157 healthy individuals, from their peripheral blood. Firstly, we compared the clinical characteristics, blood cell counts, the ratio of neutrophil-to-lymphocyte (NLR), platelet-to-lymphocyte (PLR), and CD4+/CD8+T cell count between groups. Then, we compared the diversity, clonotypes, unique VJ alleles in patients with different disease severity. Furthermore, by identifying a series of disease-associated amino acid sequences, we employed a repeated hold-out machine learning strategy to explore the optimal algorithm for calculating the TCR repertoire characteristic Index (OSA-TCI). We further confirmed its relation with clinical features by linear regression analysis. Moreover, in followup of severe OSA patients who accepted adherent non-invasive ventilation, we assessed the changes of TCR repertoires, OSA-TCI, ESS, NLR, PLR, and CD4+/CD8+T after therapy. Results We found an unexpected increase in diversity and clonotypes in the TCR repertoire of OSA patients. Furthermore, we successfully developed a novel indicator termed OSA-TCI to summarize the unique repertoire alteration, which provided 90% of sensitivity and 87% of specificity in distinguishing severe OSA. In rationalization, OSA-TCI was found correlated to AHI, BMI, hemoglobin, N1, N2 percentage of sleep, snoring, smoking and lowest oxygen saturation, but only independently related to AHI (R = 0.603) and smoking (R = 0.22). Finally, we observed OSA-TCI in the eight severe patients decreased significantly after home noninvasive ventilation for three months during follow-up, consistently in line with the TCR repertoire improvement. In contrast, NLR, PLR, and the ratio of CD4+/CD8+T cell count were found useless to diagnose and therapeutic surveillance of severe OSA. Conclusions Our study is the first to unveil the TCR repertoire alteration in OSA, indicates possible insidious autoimmune mechanisms underlying OSA, and suggests that TCR repertoires serve as a convenient peripheral blood biomarker for OSA assessment without long-time contact and facility/instrument occupation. It may shed light on future diagnostic, immunological, pathophysiological, and prognostic research on OSA.

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Aberrant DNA methylation of the toll-like receptors 2 and 6 genes in patients with obstructive sleep apnea

Cited by 9 publications

References 42 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

Molecular Pathology, Oxidative Stress, and Biomarkers in Obstructive Sleep Apnea

T cell receptor repertoire as a novel indicator for identification and immune surveillance of patients with severe obstructive sleep apnea

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