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Rheumatoid arthritis
Epithelial HIF2α expression induces intestinal barrier dysfunction and exacerbation of arthritis
  1. Jinming Wen1,
  2. Pang Lyu1,
  3. Iris Stolzer2,
  4. Jin Xu3,
  5. Andreas Gießl4,
  6. Zhen Lin1,
  7. Darja Andreev1,
  8. Katerina Kachler1,
  9. Rui Song1,
  10. Xianyi Meng1,
  11. Shan Cao1,
  12. Giuliana Guggino5,
  13. Francesco Ciccia6,
  14. Claudia Günther2,
  15. Georg Schett1,
  16. Aline Bozec1
  1. 1 Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
  2. 2 Department of Internal Medicine 1, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
  3. 3 Department of Orthopaedic Surgery, Sun Yat-Sen University, Guangzhou, China
  4. 4 Department of Animal Physiology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
  5. 5 Rheumatology Section, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University Hospital P. Giaccone, Palermo, Italy
  6. 6 Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, Napoli, Italy
  1. Correspondence to Professor Aline Bozec, Department of Internal Medicine 3, FAU, Erlangen, Germany; aline.bozec{at}uk-erlangen.de

Abstract

Objective To investigate how the mucosal barrier in the intestine influences the development of arthritis, considering that metabolic changes in the intestinal epithelium influence its barrier function.

Methods Intestinal hypoxia inducible factor (HIF)-2α expression was assessed before, at onset and during experimental arthritis and human rheumatoid arthritis (RA). Intestinal epithelial cell-specific HIF2α conditional knock-out mice were generated (HIF2α∆IEC) and subjected to collagen-induced arthritis. Clinical and histological courses of arthritis were recorded; T-cell and B-cell subsets were analysed in the gut and secondary lymphatic organs; and intestinal epithelial cells were subjected to molecular mRNA sequencing in HIF2α∆IEC and littermate control mice. The gut intestinal HIF2α target genes were delineated by chromatin immunoprecipitation and luciferase experiments. Furthermore, pharmacological HIF2α inhibitor PT2977 was used for inhibition of arthritis.

Results Intestinal HIF2α expression peaked at onset of experimental arthritis and RA. Conditionally, deletion of HIF2α in gut epithelial cells inhibited arthritis and was associated with improved intestinal barrier function and less intestinal and lymphatic Th1 and Th17 activation. Mechanistically, HIF2α induced the transcription of the pore-forming claudin (CLDN)-15, which inhibits intestinal barrier integrity. Furthermore, treatment with HIF2α inhibitor decreased claudin-15 expression in epithelial cells and inhibited arthritis.

Conclusion These findings show that the HIF2α–CLDN15 axis is critical for the breakdown of intestinal barrier function at onset of arthritis, highlighting the functional link between intestinal homeostasis and arthritis.

  • Arthritis
  • Inflammation
  • Arthritis, Experimental

Data availability statement

Data are available upon reasonable request.

https://doi.org/10.1136/annrheumdis-2021-222035

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    Data availability statement

    Data are available upon reasonable request.

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    Footnotes

    • Handling editor Josef S Smolen

    • Contributors JW and AB designed the study and wrote the manuscript; JW and PL performed the in vitro experiments; JW, PL, IS, ZL, RS, XM and SC performed the in vivo experiments; FC and GG generated the human experiments; JX analysed the RNA-seq data; DA and KK contributed to the discussion and manuscript preparation; GS and AB supervised the study, wrote the manuscript and are responsible for the overall content .

    • Funding This work was supported by the Deutsche Forschungsgemeinschaft (FOR 2886-TP02, CRC 1181 project A01 and SPP2084 µBone), the ELAN-Programme (P044) of the Universitätsklinikum Erlangen, the Interdisciplinary Centre for Clinical Research (grant F1-04) in Erlangen, the European Research Council (ERC) consolidator grant ODE and synergy grant 4D Nanoscope and the Bundesministerium für Bildung und Forschung (project MASCARA) and the ERC the IMI funded project RTCure.

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were not involved in the design, conduct, 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.