TET1 contributes to allergic airway inflammation and regulates interferon and aryl hydrocarbon receptor signaling pathways in bronchial epithelial cells

Abstract

Previous studies have suggested a role for Tet1 in the pathogenesis of childhood asthma. However, how Tet1 contributes to asthma remains unknown. Here we used mice deficient for Tet1 in a well-established model of allergic airway inflammation and demonstrated that loss of Tet1 increased disease severity including airway hyperresponsiveness and lung eosinophilia. Increased expression of Muc5ac , Il1 3 , Il33 , Il 1 7a , Egfr , and Tff 2 were observed in HDM-challenged Tet1-deficient mice compared to Tet1 +/+ littermates. Further, transcriptomic analysis of lung RNA followed by pathway and protein network analysis showed that the IFN signaling pathway was significantly upregulated and the aryl hydrocarbon receptor (AhR) pathway was significantly downregulated in HDM-challenged Tet1 −/− mice. This transcriptional regulation of the IFN and AhR pathways by Tet1 was also present in human bronchial epithelial cells at base line and following HDM challenges. Genes in these pathways were further associated with changes in DNA methylation, predicted binding of transcriptional factors with relevant functions in their promoters, and the presence of histone marks generated by histone enzymes that are known to interact with Tet1. Collectively, our data suggest that Tet1 inhibits HDM-induced allergic airway inflammation by direct regulation of the IFN and AhR pathways.

Ten-Eleven Translocation (TET) Enzymes Modulate the Activation of Dendritic Cells in Allergic Rhinitis

“…Our present study shows TET1-deficient moDCs suppressed conversion of naïve T cells into aTregs, the activated subset of regulatory T cells and are essential in maintaining immune tolerance and immune homeostasis, especially in those with AR (30). Recently, Burleson et al (43) established that HDM-challenged TET1-deficient mice have impaired interferon pathway, increased airway hyperresponsiveness, and eosinophilic infiltration in the lung. Together, this evidence suggests that the loss of TET1 induces the maturation of DCs and mediates the development of allergic airway inflammation.…”

Recent findings in the genetics and epigenetics of asthma and allergy

“…Air pollution has notably been shown to have a direct influence on the expression of enzymes involved in the balance of DNA methylation and demethylation through increasing DNA methylation levels at the promoter of the DNA demethylating enzyme TET1 [60]. Recent data in a mouse model deficient for Tet1 supports an important role for this enzyme in airway disease leading to increased expression of Th1 and Th2 cytokines, lung eosinophilia and airway hyperresponsiveness, which were at least partially mediated by a genome-wide hypermethylation including genes involved in interferon signaling [61]. Furthermore, air pollution has also shown to alter the expression profile of miRNAs involved in inflammation and which have also been associated with allergic diseases [52,62].…”

The Emerging Role of Ten-Eleven Translocation 1 in Epigenetic Responses to Environmental Exposures

“…Subsequently, we recently showed that Tet1 inhibits asthma-related phenotypes including airway hyperresponsiveness (AHR) and lung eosinophilia in mice. 44 In this HDM-induced allergic airway model, we found that Tet1, Tet2, and Tet3 were downregulated while Dnmt1, Dnmt3a, and Dnmt3b remain unchanged following the last intratracheal instillation of HDM. These changes in DNA methylation machinery are associated with DNA methylation changes in pathways such as Epithelial Adherens Junction Signaling and Leukocyte Extravasation Signaling (Zhang X and Ji H, unpublished data).…”

“…22 Meanwhile, our studies in human bronchial epithelial cells (HBECs) suggest that TET1 may interact with histone modification enzymes EZH2 and transcription factors to regulate expression of genes in the interferon signaling pathway. 44…”

“…Consistent with its role in DNA demethylation, loss of Tet1 in mouse lungs results in an increase in DNA methylation across the genome. 44 In addition, computational analysis of Tet1-regulated genes in airway epithelial cells also indicate that Tet1 may interact with transcriptional factors and histone-modifying enzymes to regulate gene expression. Taken together, these studies indicate that DEP and HDM may contribute to asthma development through regulation of Tet1, and TET1 may be a potential target to mitigate the negative impact of air pollution and allergen exposure.…”