RT Journal Article
SR Electronic
T1 Interleukin-22 orchestrates a pathological endoplasmic reticulum stress response transcriptional programme in colonic epithelial cells
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 578
OP 590
DO 10.1136/gutjnl-2019-318483
VO 69
IS 3
A1 Nick Powell
A1 Eirini Pantazi
A1 Polychronis Pavlidis
A1 Anastasia Tsakmaki
A1 Katherine Li
A1 Feifei Yang
A1 Aimee Parker
A1 Carmen Pin
A1 Domenico Cozzetto
A1 Danielle Minns
A1 Emilie Stolarczyk
A1 Svetlana Saveljeva
A1 Rami Mohamed
A1 Paul Lavender
A1 Behdad Afzali
A1 Jonathan Digby-Bell
A1 Tsui Tjir-Li
A1 Arthur Kaser
A1 Joshua Friedman
A1 Thomas T MacDonald
A1 Gavin A Bewick
A1 Graham M Lord
YR 2020
UL http://gut.bmj.com/content/69/3/578.abstract
AB 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.