1. Academic Validation
  2. Epithelial HIF2α expression induces intestinal barrier dysfunction and exacerbation of arthritis

Epithelial HIF2α expression induces intestinal barrier dysfunction and exacerbation of arthritis

  • Ann Rheum Dis. 2022 Jun 16;annrheumdis-2021-222035. doi: 10.1136/annrheumdis-2021-222035.
Jinming Wen 1 Pang Lyu 1 Iris Stolzer 2 Jin Xu 3 Andreas Gießl 4 Zhen Lin 1 Darja Andreev 1 Katerina Kachler 1 Rui Song 1 Xianyi Meng 1 Shan Cao 1 Giuliana Guggino 5 Francesco Ciccia 6 Claudia Günther 2 Georg Schett 1 Aline Bozec 7
Affiliations

Affiliations

  • 1 Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany.
  • 2 Department of Internal Medicine 1, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany.
  • 3 Department of Orthopaedic Surgery, Sun Yat-Sen University, Guangzhou, China.
  • 4 Department of Animal Physiology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany.
  • 5 Rheumatology Section, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University Hospital P. Giaccone, Palermo, Italy.
  • 6 Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, Napoli, Italy.
  • 7 Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany [email protected].
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.

Keywords

Arthritis; Arthritis, Experimental; Inflammation.

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