Objective The functional role of interleukin-22 (IL22) in chronic inflammation is controversial, and mechanistic insights into how it regulates target tissue are lacking. In this study, we evaluated the functional role of IL22 in chronic colitis and probed mechanisms of IL22-mediated regulation of colonic epithelial cells.
Design To investigate the functional role of IL22 in chronic colitis and how it regulates colonic epithelial cells, we employed a three-dimentional mini-gut epithelial organoid system, in vivo disease models and transcriptomic datasets in human IBD.
Results As well as inducing transcriptional modules implicated in antimicrobial responses, IL22 also coordinated an endoplasmic reticulum (ER) stress response transcriptional programme in colonic epithelial cells. In the colon of patients with active colonic Crohn’s disease (CD), there was enrichment of IL22-responsive transcriptional modules and ER stress response modules. Strikingly, in an IL22-dependent model of chronic colitis, targeting IL22 alleviated colonic epithelial ER stress and attenuated colitis. Pharmacological modulation of the ER stress response similarly impacted the severity of colitis. In patients with colonic CD, antibody blockade of IL12p40, which simultaneously blocks IL12 and IL23, the key upstream regulator of IL22 production, alleviated the colonic epithelial ER stress response.
Conclusions Our data challenge perceptions of IL22 as a predominantly beneficial cytokine in IBD and provide novel insights into the molecular mechanisms of IL22-mediated pathogenicity in chronic colitis. Targeting IL22-regulated pathways and alleviating colonic epithelial ER stress may represent promising therapeutic strategies in patients with colitis.
Trial registration number NCT02749630.
- Interleukin 22
- inflammatory bowel disease
- ER stress
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Contributors NP and GML conceived the study. NP designed/performed experiments, analysed data and wrote the manuscript. EP, AT (colonoids), SS (IRE1α staining), ES, DM, TT and JD-B performed experiments. Microarray data, RNA-seq, Gene Set Enrichment Analysis, Gene Set Variation Analysis and PCA were analysed by KL, FY, JRF, PL, BA, RM, PP, DC and NP. Colonoid experiments were designed by GAB and NP and were performed in GAB lab. AP and CP performed and analysed in vivo apoptosis assay. TTM helped write the paper and assessed all gut histology in a blinded fashion. All authors critically read and intellectually contributed to the manuscript.
Funding This study was supported by grants awarded by the Wellcome Trust (NP, WT101159), Guy’s and St Thomas’ Charity (NP) and Medical Research Council (GML and TTM, grant number MR/M003493/1). BA is supported by the Wellcome Trust (097261/Z/11/Z). AK is supported by WT SIA 106260/Z/14/Z and ERC HORIZON2020/ERC Grant agreement no. 648889. We are grateful to Pfizer for providing anti-IL22 antibodies, recombinant IL22 and Il22−/− mice. We acknowledge the assistance of Matt Arno (Genomics Centre, King’s College London) with gene expression microarray studies. Research was also supported by the NIHR Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust, King's College London. This project made use of time on the Rosalind high-performance computing infrastructure, funded by Guy's & St Thomas' Hospital NHS Trust Biomedical Research Centre, South London & Maudsley NHS Trust Biomedical Research Centre and the Faculty of Natural Mathematics & Science King's College London.
Disclaimer The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
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