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Original research
Vitamin D receptor and STAT6 interactome governs oesophageal epithelial barrier responses to IL-13 signalling
  1. Michael Brusilovsky1,
  2. Mark Rochman1,
  3. Tetsuo Shoda1,
  4. Michael Kotliar1,
  5. Julie M Caldwell1,
  6. Lydia E Mack1,
  7. John A Besse1,
  8. Xiaoting Chen2,
  9. Matthew T Weirauch2,3,4,
  10. Artem Barski1,4,5,
  11. Marc E Rothenberg1,4
  1. 1Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
  2. 2Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
  3. 3Divisions of Biomedical Informatics and Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
  4. 4Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
  5. 5Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
  1. Correspondence to Professor Marc E Rothenberg, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Marc.Rothenberg{at}cchmc.org

Abstract

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.

  • VITAMIN D RECEPTOR GENE
  • ALLERGY
  • FOOD ALLERGY
  • GUT INFLAMMATION
  • INFLAMMATORY MEDIATORS

Data availability statement

Data are available on reasonable request. Raw sequencing data sets are publicly available in the GEO database under GEO accession GSE184868. Sequencing data for oesophageal biopsies of patients with EoE or controls is available under GEO accession GSE58640. All figures have associated raw data. The additional data that support the findings of this study are available from the corresponding author by request.

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Data availability statement

Data are available on reasonable request. Raw sequencing data sets are publicly available in the GEO database under GEO accession GSE184868. Sequencing data for oesophageal biopsies of patients with EoE or controls is available under GEO accession GSE58640. All figures have associated raw data. The additional data that support the findings of this study are available from the corresponding author by request.

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Footnotes

  • MB and MR are joint first authors.

  • Contributors MB and MER conceived the study. MB, MR and MER designed experiments. MB, MR, JMC and LEM performed experiments and data analysis. TS performed human clinical data analysis. AB and MTW supervised bioinformatic data analysis. MK and XC performed bioinformatic data analysis. MB and MER interpreted results and wrote the manuscript. All authors read and commented on the manuscript. MER is the guarantor of this content.

  • Funding 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.).

  • Competing interests MER is a consultant for Pulm One, Spoon Guru, ClostraBio, Serpin Pharm, Allakos, Celldex, Nextstone One, Bristol Myers Squibb, Astra Zeneca, Ellodi Pharma, Glaxo Smith Kline, Regeneron/Sanofi, Revolo Biotherapeutics and Guidepoint and has an equity interest in the first seven listed and royalties from reslizumab (Teva Pharmaceuticals), PEESSv2 (Mapi Research Trust), and UpToDate. MER is an inventor of patents owned by Cincinnati Children’s Hospital Medical Center. AB is a cofounder of Datirium. MK and AB are inventors on intellectual property owned by Cincinnati Children’s Hospital Medical Center. The remaining authors declare no competing interests.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.