Epithelial HIF2α expression induces intestinal barrier dysfunction and exacerbation of arthritis

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)-2 alpha expression was assessed before, at onset and during experimental arthritis and human rheumatoid arthritis (RA). Intestinal epithelial cell-specific HIF2 alpha conditional knock-out mice were generated (HIF2 alpha(Delta 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 HIF2 alpha(Delta IEC) and littermate control mice. The gut intestinal HIF2 alpha target genes were delineated by chromatin immunoprecipitation and luciferase experiments. Furthermore, pharmacological HIF2 alpha inhibitor PT2977 was used for inhibition of arthritis. Results Intestinal HIF2 alpha expression peaked at onset of experimental arthritis and RA. Conditionally, deletion of HIF2 alpha in gut epithelial cells inhibited arthritis and was associated with improved intestinal barrier function and less intestinal and lymphatic Th1 and Th17 activation. Mechanistically, HIF2 alpha induced the transcription of the pore-forming claudin (CLDN)-15, which inhibits intestinal barrier integrity. Furthermore, treatment with HIF2 alpha inhibitor decreased claudin-15 expression in epithelial cells and inhibited arthritis. Conclusion These findings show that the HIF2 alpha-CLDN15 axis is critical for the breakdown of intestinal barrier function at onset of arthritis, highlighting the functional link between intestinal homeostasis and arthritis.