IL-20 controls resolution of experimental colitis by regulating epithelial IFN/STAT2 signalling

Chiriac MT, Hracsko Z, Günther C, Gonzalez Acera M, Atreya R, Stolzer I, Wittner L, Dressel A, Schickedanz L, Gámez Belmonte MdlR, Erkert L, Hundorfean G, Zundler S, Rath T, Vetrano S, Danese S, Sturm G, Trajanoski Z, Kühl AA, Siegmund B, Hartmann A, Wirtz S, Siebler J, Neurath-Finotto S, Becker C, Neurath M (2023)

Publication Type: Journal article

Publication year: 2023

Journal

Gut BMJ Publishing Group

Article Number: gutjnl-2023-329628

DOI: 10.1136/gutjnl-2023-329628

Abstract

Objective: We sought to investigate the role of interleukin (IL)-20 in IBD and experimental colitis. Design: Experimental colitis was induced in mice deficient in components of the IL-20 and signal transducer and activator of transcription (STAT)2 signalling pathways. In vivo imaging, high-resolution mini-endoscopy and histology were used to assess intestinal inflammation. We further used RNA-sequencing (RNA-Seq), RNAScope and Gene Ontology analysis, western blot analysis and co-immunoprecipitation, confocal microscopy and intestinal epithelial cell (IEC)-derived three-dimensional organoids to investigate the underlying molecular mechanisms. Results were validated using samples from patients with IBD and non-IBD control subjects by a combination of RNA-Seq, organoids and immunostainings. Results: In IBD, IL20 levels were induced during remission and were significantly higher in antitumour necrosis factor responders versus non-responders. IL-20RA and IL-20RB were present on IECs from patients with IBD and IL-20-induced STAT3 and suppressed interferon (IFN)-STAT2 signalling in these cells. In IBD, experimental dextran sulfate sodium (DSS)-induced colitis and mucosal healing, IECs were the main producers of IL-20. Compared with wildtype controls, Il20-/-, Il20ra-/- and Il20rb-/- mice were more susceptible to experimental DSS-induced colitis. IL-20 deficiency was associated with increased IFN/STAT2 activity in mice and IFN/STAT2-induced necroptotic cell death in IEC-derived organoids could be markedly blocked by IL-20. Moreover, newly generated Stat2ΔIEC mice, lacking STAT2 in IECs, were less susceptible to experimental colitis compared with wildtype controls and the administration of IL-20 suppressed colitis activity in wildtype animals. Conclusion: IL-20 controls colitis and mucosal healing by interfering with the IFN/STAT2 death signalling pathway in IECs. These results indicate new directions for suppressing gut inflammation by modulating IL-20-controlled STAT2 signals.

Authors with CRIS profile

Mircea-Teodor Chiriac Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Claudia Günther Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Miguel Gonzalez Acera Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Raja Atreya Professur für Translationale Immunforschung bei chronisch entzündlichen Darmerkrankungen (Heisenberg-Professur) Iris Stolzer Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Leonie Wittner Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Anja Dressel Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Laura Schickedanz Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Maria de los Reyes Gámez Belmonte Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Lena Erkert Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Sebastian Zundler Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Timo Rath Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Arndt Hartmann Lehrstuhl für Allgemeine Pathologie und Pathologische Anatomie Stefan Wirtz Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Jürgen Siebler Professur für Hepatologie Susetta Neurath-Finotto Professur für Molekulare Pneumologie Christoph Becker Professur für Molekulare Gastroenterologie Markus Neurath Lehrstuhl für Innere Medizin I

Additional Organisation(s)

Interdisziplinäres Zentrum für Klinische Forschung FAU Profilzentrum Licht.Materie.Quantentechnologien (FAU LMQ)

Related research project(s)

A078: Smurf2-dependent repression of type I IFN signalling in inflammatory bowel disease and mucosal healing Jan. 1, 2021 - Dec. 31, 2023

Involved external institutions

Medizinische Universität Innsbruck AT Austria (AT) Humanitas Research Hospital / IRCCS Istituto Clinico Humanitas IT Italy (IT) Ospedale San Raffaele (früher: Centro San Raffaele del Monte Tabor Foundation) IT Italy (IT) Charité - Universitätsmedizin Berlin DE Germany (DE) Freie Universität Berlin DE Germany (DE)

How to cite

APA:

Chiriac, M.-T., Hracsko, Z., Günther, C., Gonzalez Acera, M., Atreya, R., Stolzer, I.,... Neurath, M. (2023). IL-20 controls resolution of experimental colitis by regulating epithelial IFN/STAT2 signalling. Gut. https://doi.org/10.1136/gutjnl-2023-329628

MLA:

Chiriac, Mircea-Teodor, et al. "IL-20 controls resolution of experimental colitis by regulating epithelial IFN/STAT2 signalling." Gut (2023).

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