Epithelial HIF2 alpha expression induces intestinal barrier dysfunction and exacerbation of arthritis

Wen J, Lyu P, Stolzer I, Xu J, Gießl A, Lin Z, Andreev D, Kachler K, Song R, Meng X, Cao S, Guggino G, Ciccia F, Günther C, Schett G, Bozec A (2022)

Publication Language: English

Publication Type: Journal article

Publication year: 2022

Journal

Annals of the Rheumatic Diseases BMJ Publishing Group

URI: https://ard.bmj.com/content/81/8/1119

DOI: 10.1136/annrheumdis-2021-222035

Abstract

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. 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 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. 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.

Authors with CRIS profile

Jinming Wen Department of Medicine 3 – Rheumatology and Immunology Pang Lyu Professur für Experimentelle Immuntherapie Iris Stolzer Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Andreas Gießl Lehrstuhl für Tierphysiologie Zhen Lin Professur für Experimentelle Immuntherapie Darja Andreev Department of Medicine 3 – Rheumatology and Immunology Katerina Kachler Department of Medicine 3 – Rheumatology and Immunology Rui Song Department of Medicine 3 – Rheumatology and Immunology Xianyi Meng Shan Cao Professur für Experimentelle Immuntherapie Claudia Günther Professur für Gastrointestinale Pathophysiologie Georg Schett Lehrstuhl für Innere Medizin III Aline Bozec Professur für Experimentelle Immuntherapie

Additional Organisation(s)

Interdisziplinäres Zentrum für Klinische Forschung (IZKF)

Related research project(s)

A077: HIF pathway activation in B cells regulates postmenopausal bone loss Dec. 16, 2020 - Dec. 15, 2023

Involved external institutions

University Medical Clinic Palermo / Azienda Ospedaliera Universitaria Policlinico Palermo IT Italy (IT) Sun Yat-Sen University CN China (CN) Università degli studi della Campania Luigi Vanvitelli IT Italy (IT)

How to cite

APA:

Wen, J., Lyu, P., Stolzer, I., Xu, J., Gießl, A., Lin, Z.,... Bozec, A. (2022). Epithelial HIF2 alpha expression induces intestinal barrier dysfunction and exacerbation of arthritis. Annals of the Rheumatic Diseases. https://doi.org/10.1136/annrheumdis-2021-222035

MLA:

Wen, Jinming, et al. "Epithelial HIF2 alpha expression induces intestinal barrier dysfunction and exacerbation of arthritis." Annals of the Rheumatic Diseases (2022).

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