Dataset Information

Epigenetics of chronic rhinosinusitis and the role of the eosinophil.

ABSTRACT:

Background

One theory for the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP) involves aberration in the expression of genes that maintain the sinonasal innate immune system. We propose that the alteration in gene expression seen in CRSwNP is a result of oxidative byproducts of eosinophils. Activated eosinophils and neutrophils may lead to the production of hypobromous acid (HOBr) and hypochlorous acid (HOCL) and the posttranslational modification products 5-bromocytosine (5BrC) and 5-chlorocytosine (5ClC), respectively. 5BrC and 5ClC may cause aberrant methylation of cytosine during DNA replication and mimic the endogenous methylation signal associated with gene silencing. We propose to use gas chromatography-mass spectrometry (GC-MS) to identify the presence of 5BrC and 5ClC in CRSwNP patients.

Methods

Patients with CRSwNP undergoing endoscopic sinus surgery were prospectively recruited into this study. Using GC-MS, tissue specimens were analyzed for the presence of 5BrC, 5ClC, and methylated cytosine.

Results

Tissue specimens from 14 patients with CRSwNP and 3 normal controls were processed using GC-MS. CRSwNP specimens demonstrate elevated levels of 5BrC and 5ClC compared to normal controls.

Conclusion

Eosinophils, which are predominantly found in CRSwNP, may lead to DNA modification and gene silencing via 5BrC and aberrant methylation patterns and may help explain the pathogenesis of CRSwNP.

SUBMITTER: Seiberling KA

PROVIDER: S-EPMC4241761 | biostudies-literature | 2012 Jan-Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Epigenetics of chronic rhinosinusitis and the role of the eosinophil.

Seiberling Kristin A KA Church Christopher A CA Herring Jason L JL Sowers Lawrence C LC

International forum of allergy & rhinology 20110826 1

<h4>Background</h4>One theory for the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP) involves aberration in the expression of genes that maintain the sinonasal innate immune system. We propose that the alteration in gene expression seen in CRSwNP is a result of oxidative byproducts of eosinophils. Activated eosinophils and neutrophils may lead to the production of hypobromous acid (HOBr) and hypochlorous acid (HOCL) and the posttranslational modification products 5-bromocytosi ...[more]

PMID: 22311846

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Project description:Background Epigenetics facilitates insights on the impact of host environment on the genesis of chronic rhinosinusitis (CRS) through modulations of host gene expression and activity. Epigenetic mechanisms such as DNA methylation cause reversible but heritable changes in gene expression over generations of progeny, without altering the DNA base-pair sequences. These studies offer a critical understanding of the environment-induced changes that result in host predisposition to disease and may help in developing novel biomarkers and therapeutics. The goal of this systematic review is to summarize the current evidence on epigenetics of CRS with a focus on chronic rhinosinusitis with nasal polyps (CRSwNP) and highlight gaps that merit further research. Methods A systematic review of the English language literature was performed to identify investigations related to epigenetic studies in subjects with CRS. Results The review identified 65 studies. These have focused on DNA methylation and non-coding RNAs, with only a few on histone deacetylation, alternative polyadenylation, and chromatin accessibility. Studies include those investigating in vivo and in vitro changes or both. Studies also include animal models of CRS. Almost all have been conducted in Asia. The genome-wide studies of DNA methylation found differences in global methylation between CRSwNP and controls, while others specifically found significant differences in methylation of the CpG sites of the thymic stromal lymphopoietin (TSLP), IL-8, and PLAT. In addition, DNA methyltransferase inhibitors and histone deacetylase inhibitors were studied as potential therapeutic agents. Majority of the studies investigating non-coding RNAs focused on micro-RNAs (miRNA) and found differences in global expression of miRNA levels. These studies also revealed some previously known as well as novel targets and pathways such as tumor necrosis factor alpha, TGF beta-1, IL-10, EGR2, aryl hydrocarbon receptor, PI3K/AKT pathway, mucin secretion, and vascular permeability. Overall, the studies have found a dysregulation in pathways/genes involving inflammation, immune regulation, tissue remodeling, structural proteins, mucin secretion, arachidonic acid metabolism, and transcription. Conclusions Epigenetic studies in CRS subjects suggest that there is likely a major impact of the environment. However, these are association studies and do not directly imply pathogenesis. Longitudinal studies in geographically and racially diverse population cohorts are necessary to quantify genetic vs. environmental risks for CRSwNP and CRS without nasal polyps and assess heritability risk, as well as develop novel biomarkers and therapeutic agents.

Project description:BackgroundUncontrolled severe eosinophilic chronic rhinosinusitis (eCRS) is associated with elevated levels of Th2 cells and raised immunoglobulin concentrations in nasal polyp tissue. eCRS is characterized by high eosinophilic infiltration and type 2 inflammation. Gαi1/3 proteins participate in allergic inflammation by regulating immune cells. Whether Gαi1/3 proteins have a role in the development of eCRS remains unknown.ObjectivesTo investigate the association between Gαi1/3 expression levels and CRS and the underlying mechanisms.MethodsWestern blotting and immunohistology were used to detect Gαi1/3 expression. Correlations between Gαi1/3 and immune cells and clinical parameters were analyzed. Signaling pathway activation in IL-5-induced Gαi1/3-knockout or knockdown mouse embryonic fibroblasts (MEFs) and eosinophils (EoL-1 cells) was detected by western blotting. EdU/DAPI was used to evaluate the proliferation of EoL-1 cells. A CRS model was established using Gαi1/3-knockout mice, and histological analysis and inflammatory cytokine measurements were performed.ResultsCompared with the non-eCRS subset, the eCRS subset showed significantly increased Gαi1/3 expression levels. High nasal tissue Gαi1/3 levels were linked to high tissue eosinophil infiltration, and high disease severity and allergic conditions in CRS patients. Gαi1/3 were required for IL-5-induced Akt-mTOR and Erk activation in MEFs. In EoL-1 cells, Gαi1/3 was associated with IL-5-activated IL-5Rα, promoting IL-5Rα endocytosis and transducing downstream signaling. IL-5-induced EoL-1 cell proliferation and degranulation were suppressed after Gαi1/3 silencing. In a CRS murine model, immune cell infiltration and type 2 inflammation were largely impaired in Gαi1/3-double-knockout mice.ConclusionIncreased Gαi1/3 expression levels in nasal tissue are linked to eosinophil infiltration and increased disease severity in CRS patients. Gαi1/3 contributes to eosinophil activation and participates in regulating allergic inflammation in CRS patients.

Project description:BackgroundChronic rhinosinusitis with nasal polyps (CRSwNP) is likely to relapse due to aberrant eosinophil infiltration. The deficiency of Vitamin D (VD) is associated with increased eosinophil infiltration in eosinophilic oesophagitis. However, the role of VD in eosinophilic CRSwNP (ECRSwNP) remains unclear. This study aims to explore the effects of VD on eosinophil chemotaxis in ECRSwNP and the underlying mechanisms.MethodsHuman nasal mucosal tissues were collected from the control group, patients with non-ECRSwNP and those with ECRSwNP. Enzyme-linked immunosorbent assay (ELISA) was used to detect the expression of VD and CCL26 in the nasal mucosa, plasma, or human primary nasal epithelial cells (hNECs). hNECs and eosinophils from patients were cultured to investigate the effect of VD on eosinophil chemotaxis and CCL26 expression via eosinophil migration assay, Western blot, and ELISA. Transcriptome sequencing, pathway enrichment analysis, Western blot and immunohistochemical staining were used to determine the key signaling pathway involved in eosinophil chemotaxis.ResultsA significant decrease in VD levels was observed in the nasal mucosa of patients with ECRSwNP, which correlated with increased local eosinophil infiltration. Furthermore, pathway enrichment analysis suggested that glycolysis signaling was promoted in the ECRSwNP group, verified by enhanced expression of glycolytic key enzymes that were positively correlated with eosinophil infiltration in nasal mucosa from patients with ECRSwNP. VD suppressed eosinophil chemotaxis in vitro by inhibiting CCL26 expression. Glycolysis regulated CCL26 expression via the ERK pathway and lactate, which promoted the expression and stability of CCL26 protein. VD attenuated glycolysis, leading to decreased production of lactate and inactivation of the ERK pathway. The decrease in lactate production suppressed eosinophil chemotaxis. Moreover, the ERK pathway activator reversed the inhibitory effect of VD on eosinophil chemotaxis.ConclusionsVD impedes eosinophil chemotaxis by inhibiting glycolysis - induced CCL26 expression via attenuating the activation of the ERK pathway and reducing lactate production. VD supplementation may be a novel strategy to treat ECRSwNP.

Dataset Information

Epigenetics of chronic rhinosinusitis and the role of the eosinophil.

Background

Methods

Results

Conclusion

Publications

Epigenetics of chronic rhinosinusitis and the role of the eosinophil.

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