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

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...

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Autores principales: Powell, Nick, Pantazi, Eirini, Pavlidis, Polychronis, Tsakmaki, Anastasia, Li, Katherine, Yang, Feifei, Parker, Aimee, Pin, Carmen, Cozzetto, Domenico, Minns, Danielle, Stolarczyk, Emilie, Saveljeva, Svetlana, Mohamed, Rami, Lavender, Paul, Afzali, Behdad, Digby-Bell, Jonathan, Tjir-Li, Tsui, Kaser, Arthur, Friedman, Joshua, MacDonald, Thomas T, Bewick, Gavin A, Lord, Graham M
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034350/
https://www.ncbi.nlm.nih.gov/pubmed/31792136
http://dx.doi.org/10.1136/gutjnl-2019-318483
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author Powell, Nick
Pantazi, Eirini
Pavlidis, Polychronis
Tsakmaki, Anastasia
Li, Katherine
Yang, Feifei
Parker, Aimee
Pin, Carmen
Cozzetto, Domenico
Minns, Danielle
Stolarczyk, Emilie
Saveljeva, Svetlana
Mohamed, Rami
Lavender, Paul
Afzali, Behdad
Digby-Bell, Jonathan
Tjir-Li, Tsui
Kaser, Arthur
Friedman, Joshua
MacDonald, Thomas T
Bewick, Gavin A
Lord, Graham M
author_facet Powell, Nick
Pantazi, Eirini
Pavlidis, Polychronis
Tsakmaki, Anastasia
Li, Katherine
Yang, Feifei
Parker, Aimee
Pin, Carmen
Cozzetto, Domenico
Minns, Danielle
Stolarczyk, Emilie
Saveljeva, Svetlana
Mohamed, Rami
Lavender, Paul
Afzali, Behdad
Digby-Bell, Jonathan
Tjir-Li, Tsui
Kaser, Arthur
Friedman, Joshua
MacDonald, Thomas T
Bewick, Gavin A
Lord, Graham M
author_sort Powell, Nick
collection PubMed
description 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.
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spelling pubmed-70343502020-03-03 Interleukin-22 orchestrates a pathological endoplasmic reticulum stress response transcriptional programme in colonic epithelial cells Powell, Nick Pantazi, Eirini Pavlidis, Polychronis Tsakmaki, Anastasia Li, Katherine Yang, Feifei Parker, Aimee Pin, Carmen Cozzetto, Domenico Minns, Danielle Stolarczyk, Emilie Saveljeva, Svetlana Mohamed, Rami Lavender, Paul Afzali, Behdad Digby-Bell, Jonathan Tjir-Li, Tsui Kaser, Arthur Friedman, Joshua MacDonald, Thomas T Bewick, Gavin A Lord, Graham M Gut Recent Advances in Basic Science 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. BMJ Publishing Group 2020-03 2019-12-02 /pmc/articles/PMC7034350/ /pubmed/31792136 http://dx.doi.org/10.1136/gutjnl-2019-318483 Text en © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.
spellingShingle Recent Advances in Basic Science
Powell, Nick
Pantazi, Eirini
Pavlidis, Polychronis
Tsakmaki, Anastasia
Li, Katherine
Yang, Feifei
Parker, Aimee
Pin, Carmen
Cozzetto, Domenico
Minns, Danielle
Stolarczyk, Emilie
Saveljeva, Svetlana
Mohamed, Rami
Lavender, Paul
Afzali, Behdad
Digby-Bell, Jonathan
Tjir-Li, Tsui
Kaser, Arthur
Friedman, Joshua
MacDonald, Thomas T
Bewick, Gavin A
Lord, Graham M
Interleukin-22 orchestrates a pathological endoplasmic reticulum stress response transcriptional programme in colonic epithelial cells
title Interleukin-22 orchestrates a pathological endoplasmic reticulum stress response transcriptional programme in colonic epithelial cells
title_full Interleukin-22 orchestrates a pathological endoplasmic reticulum stress response transcriptional programme in colonic epithelial cells
title_fullStr Interleukin-22 orchestrates a pathological endoplasmic reticulum stress response transcriptional programme in colonic epithelial cells
title_full_unstemmed Interleukin-22 orchestrates a pathological endoplasmic reticulum stress response transcriptional programme in colonic epithelial cells
title_short Interleukin-22 orchestrates a pathological endoplasmic reticulum stress response transcriptional programme in colonic epithelial cells
title_sort interleukin-22 orchestrates a pathological endoplasmic reticulum stress response transcriptional programme in colonic epithelial cells
topic Recent Advances in Basic Science
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034350/
https://www.ncbi.nlm.nih.gov/pubmed/31792136
http://dx.doi.org/10.1136/gutjnl-2019-318483
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