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

Autor: Behdad Afzali, Joshua R. Friedman, Domenico Cozzetto, Svetlana Saveljeva, Feifei Yang, Anastasia Tsakmaki, Rami Mohamed, Tsui Tjir-Li, Katherine Li, Emilie Stolarczyk, Thomas T. MacDonald, Aimee Parker, Polychronis Pavlidis, Carmen Pin, Gavin A. Bewick, Arthur Kaser, Eirini Pantazi, Danielle Minns, Graham M. Lord, Nick Powell, Jonathan Digby-Bell, Paul Lavender
Přispěvatelé: Powell, Nick [0000-0003-3231-6950], Pavlidis, Polychronis [0000-0003-4864-2208], Friedman, Joshua [0000-0001-9382-8429], Bewick, Gavin A [0000-0002-4335-8403], Apollo - University of Cambridge Repository, Wellcome Trust
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
Transcription
Genetic
Apoptosis
THERAPY
Inflammatory bowel disease
Interleukin-23
DISEASE
Interleukin 22
Mice
0302 clinical medicine
Crohn Disease
Medicine
Intestinal Mucosa
INDUCED APOPTOSIS
Gastrointestinal agent
INDUCTION
Tunicamycin
Interleukin-17
Gastroenterology
Colitis
Endoplasmic Reticulum Stress
Phenylbutyrates
Recombinant Proteins
3. Good health
Anti-Bacterial Agents
Organoids
030220 oncology & carcinogenesis
Ustekinumab
medicine.symptom
ER stress
Life Sciences & Biomedicine
INTESTINAL INFLAMMATION
Cell Survival
Colon
INNATE LYMPHOID-CELLS
Inflammation
Phenylbutyrate
MECHANISMS
03 medical and health sciences
Gastrointestinal Agents
inflammatory bowel disease
Animals
Humans
Science & Technology
Gastroenterology & Hepatology
business.industry
Endoplasmic reticulum
Interleukins
Recent Advances in Basic Science
Patient Acuity
1103 Clinical Sciences
Epithelial Cells
medicine.disease
digestive system diseases
Disease Models
Animal
030104 developmental biology
PROTECT
Chronic Disease
Unfolded protein response
Cancer research
Unfolded Protein Response
1114 Paediatrics and Reproductive Medicine
business
Zdroj: Powell, N, Pantazi, E, Pavlidis, P, Tsakmaki, A, Li, K, Yang, F, Parker, A, Pin, C, Cozzetto, D, Minns, D, Stolarczyk, E, Saveljeva, S, Mohamed, R, Lavender, P, Afzali, B, Digby-Bell, J, Tjir-Li, T, Kaser, A, Friedman, J, MacDonald, T T, Bewick, G A & Lord, G M 2020, ' Interleukin-22 orchestrates a pathological endoplasmic reticulum stress response transcriptional programme in colonic epithelial cells ', Gut, vol. 69, no. 3, pp. 578-590 . https://doi.org/10.1136/gutjnl-2019-318483
Gut
Popis: ObjectiveThe 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.DesignTo 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.ResultsAs 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.ConclusionsOur 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 numberNCT02749630.
Databáze: OpenAIRE
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