TY - JOUR
T1 - Vitamin D receptor and STAT6 interactome governs oesophageal epithelial barrier responses to IL-13 signalling
AU - Brusilovsky, Michael
AU - Rochman, Mark
AU - Shoda, Tetsuo
AU - Kotliar, Michael
AU - Caldwell, Julie M.
AU - Mack, Lydia E.
AU - Besse, John A.
AU - Chen, Xiaoting
AU - Weirauch, Matthew T.
AU - Barski, Artem
AU - Rothenberg, Marc E.
N1 - Funding Information:
This work was supported in part by NIH R01AI045898, R01AI130033, R01AI123176, and R01AI113125; the Campaign Urging Research for Eosinophilic Disease (CURED); and the Sunshine Charitable Foundation and its supporters, Denise and David Bunning (M.E.R.).
Publisher Copyright:
© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.
PY - 2022/1/1
Y1 - 2022/1/1
N2 - Objective: The contribution of vitamin D (VD) deficiency to the pathogenesis of allergic diseases remains elusive. We aimed to define the impact of VD on oesophageal allergic inflammation. Design: We assessed the genomic distribution and function of VD receptor (VDR) and STAT6 using histology, molecular imaging, motif discovery and metagenomic analysis. We examined the role of VD supplementation in oesophageal epithelial cells, in a preclinical model of IL-13-induced oesophageal allergic inflammation and in human subjects with eosinophilic oesophagitis (EoE). Results: VDR response elements were enriched in oesophageal epithelium, suggesting enhanced VDR binding to functional gene enhancer and promoter regions. Metagenomic analysis showed that VD supplementation reversed dysregulation of up to 70% of the transcriptome and epigenetic modifications (H3K27Ac) induced by IL-13 in VD-deficient cells, including genes encoding the transcription factors HIF1A and SMAD3, endopeptidases (SERPINB3) and epithelial-mesenchymal transition mediators (TGFBR1, TIAM1, SRC, ROBO1, CDH1). Molecular imaging and chromatin immunoprecipitation showed VDR and STAT6 colocalisation within the regulatory regions of the affected genes, suggesting that VDR and STAT6 interactome governs epithelial tissue responses to IL-13 signalling. Indeed, VD supplementation reversed IL-13-induced epithelial hyperproliferation, reduced dilated intercellular spaces and barrier permeability, and improved differentiation marker expression (filaggrin, involucrin). In a preclinical model of IL-13-mediated oesophageal allergic inflammation and in human EoE, VD levels inversely associated with severity of oesophageal eosinophilia and epithelial histopathology. Conclusions: Collectively, these findings identify VD as a natural IL-13 antagonist with capacity to regulate the oesophageal epithelial barrier functions, providing a novel therapeutic entry point for type 2 immunity-related diseases.
AB - Objective: The contribution of vitamin D (VD) deficiency to the pathogenesis of allergic diseases remains elusive. We aimed to define the impact of VD on oesophageal allergic inflammation. Design: We assessed the genomic distribution and function of VD receptor (VDR) and STAT6 using histology, molecular imaging, motif discovery and metagenomic analysis. We examined the role of VD supplementation in oesophageal epithelial cells, in a preclinical model of IL-13-induced oesophageal allergic inflammation and in human subjects with eosinophilic oesophagitis (EoE). Results: VDR response elements were enriched in oesophageal epithelium, suggesting enhanced VDR binding to functional gene enhancer and promoter regions. Metagenomic analysis showed that VD supplementation reversed dysregulation of up to 70% of the transcriptome and epigenetic modifications (H3K27Ac) induced by IL-13 in VD-deficient cells, including genes encoding the transcription factors HIF1A and SMAD3, endopeptidases (SERPINB3) and epithelial-mesenchymal transition mediators (TGFBR1, TIAM1, SRC, ROBO1, CDH1). Molecular imaging and chromatin immunoprecipitation showed VDR and STAT6 colocalisation within the regulatory regions of the affected genes, suggesting that VDR and STAT6 interactome governs epithelial tissue responses to IL-13 signalling. Indeed, VD supplementation reversed IL-13-induced epithelial hyperproliferation, reduced dilated intercellular spaces and barrier permeability, and improved differentiation marker expression (filaggrin, involucrin). In a preclinical model of IL-13-mediated oesophageal allergic inflammation and in human EoE, VD levels inversely associated with severity of oesophageal eosinophilia and epithelial histopathology. Conclusions: Collectively, these findings identify VD as a natural IL-13 antagonist with capacity to regulate the oesophageal epithelial barrier functions, providing a novel therapeutic entry point for type 2 immunity-related diseases.
KW - ALLERGY
KW - FOOD ALLERGY
KW - GUT INFLAMMATION
KW - INFLAMMATORY MEDIATORS
KW - VITAMIN D RECEPTOR GENE
UR - http://www.scopus.com/inward/record.url?scp=85135955787&partnerID=8YFLogxK
U2 - 10.1136/gutjnl-2022-327276
DO - 10.1136/gutjnl-2022-327276
M3 - Article
C2 - 35918104
AN - SCOPUS:85135955787
JO - Gut
JF - Gut
SN - 0017-5749
M1 - 327276
ER -
