King's College London

Research portal

Interleukin-22 orchestrates a pathological endoplasmic reticulum stress response transcriptional programme in colonic epithelial cells

Research output: Contribution to journalReview article

Nick Powell, Eirini Pantazi, Polychronis Pavlidis, Anastasia Tsakmaki, Katherine Li, Feifei Yang, Aimee Parker, Carmen Pin, Domenico Cozzetto, Danielle Minns, Emilie Stolarczyk, Svetlana Saveljeva, Rami Mohamed, Paul Lavender, Behdad Afzali, Jonathan Digby-Bell, Tsui Tjir-Li, Arthur Kaser, Joshua Friedman, Thomas T MacDonald & 2 more Gavin A Bewick, Graham M Lord

Original languageEnglish
Pages (from-to)578-590
Number of pages13
JournalGut
Volume69
Issue number3
Early online date2 Dec 2019
DOIs
Publication statusPublished - 7 Feb 2020

Bibliographical note

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.

Documents

King's Authors

Abstract

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.

Download statistics

No data available

View graph of relations

© 2018 King's College London | Strand | London WC2R 2LS | England | United Kingdom | Tel +44 (0)20 7836 5454