2. Academic Validation
  3. Expression of HIF1α in intestinal epithelium restricts arthritis inflammation by inhibiting RIPK3-induced cell death machinery

Expression of HIF1α in intestinal epithelium restricts arthritis inflammation by inhibiting RIPK3-induced cell death machinery

  • Ann Rheum Dis. 2024 Mar 19:ard-2023-224491. doi: 10.1136/ard-2023-224491.
Pang Lyu # 1 2,  Jinming Wen # 1 2,  Wenshuo Zhang 1 2,  Ning Liu 1 2,  Iris Stolzer 2 3,  Andreas Gießl 4,  Yewei Jia 1 2,  Daniele Mauro 5,  Fulin Zhang 1 2,  Francesco Ciccia 5,  Didier Soulat 6,  Claudia Günther 2 3,  Georg Schett 1 2,  Aline Bozec 7 2
Affiliations

Affiliations

  • 1 Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany.
  • 2 Deutsches Zentrum Immuntherapie, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany.
  • 3 Department of Internal Medicine 1, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Bayern, Germany.
  • 4 Department of Opthalmology, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany.
  • 5 Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, Napoli, Campania, Italy.
  • 6 Microbiology Institute, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany.
  • 7 Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany [email protected].
  • # Contributed equally.
PMID: 38503474 DOI: 10.1136/ard-2023-224491
Abstract

Objectives: To investigate the mechanism by which intestinal epithelial cell (IEC) death induces arthritis.

Methods: IEC death was assessed by staining for Necroptosis and Apoptosis markers and fluorescence in situ hybridisation at different time points during collagen-induced arthritis (CIA). During the development of CIA, messenger RNA (mRNA) sequencing was performed, followed by Gene Ontology enrichment analysis of differentially expressed genes. Mice deficient for hypoxia-inducible factor 1α (Hif1a) in IECs (Hif1a ∆IEC) were generated and induced for arthritis. mRNA sequencing, chromatin immunoprecipitated (ChIP) DNA sequencing and ChIP-qualitative PCR were performed on IECs from Hif1a ∆IEC mice and littermate controls. Effects of HIF1α stabilisation by inhibition of prolyl hydroxylase domain-containing enzymes and treatment with the inhibitor of receptor-interacting protein kinase-3 (RIPK3) were tested in intestinal organoids and in CIA.

Results: IEC underwent apoptotic and necroptotic cell death at the onset of arthritis, leading to impaired gut barrier function. HIF1α was identified as one of the most upregulated genes in IECs during the onset of arthritis. Deletion of Hif1a in IEC enhanced IEC Necroptosis, triggered intestinal inflammation and exacerbated arthritis. HIF1α was found to be a key transcriptional repressor for the necroptosis-inducing factor RIPK3. Enhanced RIPK3 expression, indicating Necroptosis, was also found in the intestinal epithelium of patients with new-onset rheumatoid arthritis. Therapeutic stabilisation of HIF1α as well as small-molecule-based RIPK3 inhibition rescued intestinal Necroptosis in vitro and in vivo and suppressed the development of arthritis.

Conclusion: Our results identify IEC Necroptosis as a critical link between the gut and the development of arthritis.

Keywords

Arthritis, Experimental; Arthritis, Rheumatoid; Immune System Diseases; Inflammation.

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