Interleukin-4 Induces CpG Site-Specific Demethylation of the Pendrin Promoter in Primary Human Bronchial Epithelial Cells

Scantamburlo, Giada; Vanoni, Simone; Dossena, Silvia; Soyal, Selma M.; Bernardinelli, Emanuele; Civello, Davide Antonio; Patsch, Wolfgang; Paulmichl, Markus; Nofziger, Charity

doi:10.1159/000470720

Cited by 12 publications

(8 citation statements)

References 37 publications

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“…This suggests that ASL HCO 3 − content and pH homeostasis involve transporters other than CFTR. Our results show that pendrin, an electroneutral anion exchanger, contributes to ASL pH regulation, and point to its functional defect in the context of the F508del genotype in epithelial respiratory cells 19,29–31 . Indeed, pendrin has an important role in airways for ASL hydration and has already been involved in asthma and other inflammatory airway diseases 30,32–35 .…”

Section: Discussionmentioning

confidence: 62%

Airway surface liquid acidification initiates host defense abnormalities in Cystic Fibrosis

Simonin

Bille

Crambert

et al. 2019

Sci Rep

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Cystic fibrosis (CF) is caused by defective Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein. Morbidity is mainly due to early airway infection. We hypothesized that S. aureus clearance during the first hours of infection was impaired in CF human Airway Surface Liquid (ASL) because of a lowered pH. The ASL pH of human bronchial epithelial cell lines and primary respiratory cells from healthy controls (WT) and patients with CF was measured with a pH microelectrode. The antimicrobial capacity of airway cells was studied after S. aureus apical infection by counting surviving bacteria. ASL was significantly more acidic in CF than in WT respiratory cells. This was consistent with a defect in bicarbonate secretion involving CFTR and SLC26A4 (pendrin) and a persistent proton secretion by ATP12A. ASL demonstrated a defect in S. aureus clearance which was improved by pH normalization. Pendrin inhibition in WT airways recapitulated the CF airway defect and increased S. aureus proliferation. ATP12A inhibition by ouabain decreased bacterial proliferation. Antimicrobial peptides LL-37 and hBD1 demonstrated a pH-dependent activity. Normalizing ASL pH might improve innate airway defense in newborns with CF during onset of S. aureus infection. Pendrin activation and ATP12A inhibition could represent novel therapeutic strategies to normalize pH in CF airways.

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Section: Discussionmentioning

confidence: 62%

Airway surface liquid acidification initiates host defense abnormalities in Cystic Fibrosis

Simonin

Bille

Crambert

et al. 2019

Sci Rep

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“…Thiocyanate is subjected to oxidation generating hypothiocyanite (OSCN − ), which holds antibacterial functions in the airway surface liquid (ASL), but also exhibits pro-inflammatory activity [40]. In human bronchial epithelial cells, treatment with IL4 stimulated the expression of pendrin, which mediates SCN − transport [4], possibly by inducing the demethylation of pendrin promoter [41]. Using the microarrays technology, the pendrin gene has been identified as an IL13-inducible gene in human airway epithelial cells.…”

Section: Pendrin Expression and Function In The Airwaysmentioning

confidence: 99%

Functional interplay between CFTR and pendrin: physiological and pathophysiological relevance

Tamma¹,

Dossena²

2022

Front. Biosci. (Landmark Ed)

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The transport of chloride and bicarbonate across epithelia controls the pH and volume of the intracellular and luminal fluids, as well as the systemic pH and vascular volume. The anion exchanger pendrin (SLC26A4) and the cystic fibrosis transmembrane conductance regulator (CFTR) channel are expressed in the apical membrane of epithelial cells of various organs and tissues, including the airways, kidney, thyroid, and inner ear. While pendrin drives chloride reabsorption and bicarbonate, thiocyanate or iodide secretion within the apical compartment, CFTR represents a pathway for the apical efflux of chloride, bicarbonate, and possibly iodide. In the airways, pendrin and CFTR seems to be involved in alkalinization of the apical fluid via bicarbonate secretion, especially during inflammation, while CFTR also controls the volume of the apical fluid via a cAMP-dependent chloride secretion, which is stimulated by pendrin. In the kidney, pendrin is expressed in the cortical collecting duct and connecting tubule and co-localizes with CFTR in the apical membrane of β intercalated cells. Bicarbonate secretion occurs via pendrin, which also drives chloride reabsorption. A functional CFTR is required for pendrin activity. Whether CFTR stimulates pendrin via a direct molecular interaction or other mechanisms, or simply provides a pathway for chloride recycling across the apical membrane remains to be established. In the thyroid, CFTR and pendrin might have overlapping functions in driving the apical flux of iodide within the follicular lumen. In other organs, including the inner ear, the possible functional interplay between pendrin and CFTR needs to be explored.

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“…Similar spatial analysis of DNA methylation combined with gene expression profiling could immensely contribute to a better understanding of the effects observed in studies of whole tissue samples. Demethylation of specific CpG sites has been observed as a consequence of transcription factor binding during inflammatory responses, leading to the heterogenic methylation pattern within certain promoters [100,101]. The application of different methylation-sensitive enzymes revealed the heterogeneity of DNA methylation within the TLR2 promoter in the gingival tissue [83].…”

Section: Increased Numbers Of Inflammatory Cells Are Associatedmentioning

confidence: 99%

Epigenetic regulation of inflammation in periodontitis: cellular mechanisms and therapeutic potential

2020

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Epigenetic mechanisms, namely DNA and histone modifications, are critical regulators of immunity and inflammation which have emerged as potential targets for immunomodulating therapies. The prevalence and significant morbidity of periodontitis, in combination with accumulating evidence that genetic, environmental and lifestyle factors cannot fully explain the susceptibility of individuals to disease development, have driven interest in epigenetic regulation as an important factor in periodontitis pathogenesis. Aberrant promoter methylation profiles of genes involved in inflammatory activation, including TLR2, PTGS2, IFNG, IL6, IL8, and TNF, have been observed in the gingival tissue, peripheral blood or buccal mucosa from patients with periodontitis, correlating with changes in expression and disease severity. The expression of enzymes that regulate histone acetylation, in particular histone deacetylases (HDACs), is also dysregulated in periodontitis-affected gingival tissue. Infection of gingival epithelial cells, gingival fibroblasts and periodontal ligament cells with the oral pathogens Porphyromonas gingivalis or Treponema denticola induces alterations in expression and activity of chromatin-modifying enzymes, as well as site-specific and global changes in DNA methylation profiles and in histone acetylation and methylation marks. These epigenetic changes are associated with excessive production of inflammatory cytokines, chemokines, and matrix-degrading enzymes that can be suppressed by small molecule inhibitors of HDACs (HDACi) or DNA methyltransferases. HDACi and inhibitors of bromodomain-containing BET proteins ameliorate inflammation, osteoclastogenesis, and alveolar bone resorption in animal models of periodontitis, suggesting their clinical potential as host modulation therapeutic agents. However, broader application of epigenomic methods will be required to create a comprehensive map of epigenetic changes in periodontitis. The integration of functional studies with global analyses of the epigenetic landscape will provide critical information on the therapeutic and diagnostic potential of epigenetics in periodontal disease.

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Interleukin-4 Induces CpG Site-Specific Demethylation of the Pendrin Promoter in Primary Human Bronchial Epithelial Cells

Cited by 12 publications

References 37 publications

Airway surface liquid acidification initiates host defense abnormalities in Cystic Fibrosis

Airway surface liquid acidification initiates host defense abnormalities in Cystic Fibrosis

Functional interplay between CFTR and pendrin: physiological and pathophysiological relevance

Epigenetic regulation of inflammation in periodontitis: cellular mechanisms and therapeutic potential

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