E-type prostanoid receptor 4 drives resolution of intestinal inflammation by blocking epithelial necroptosis

Patankar J, Muller TM, Kantham S, Acera MG, Mascia F, Scheibe K, Mahapatro M, Heichler C, Yu Y, Li W, Ruder B, Günther C, Leppkes M, Mathew MJ, Wirtz S, Neufert C, Kuhl AA, Paquette J, Jacobson K, Atreya R, Zundler S, Neurath M, Young RN, Becker C (2021)

Publication Language: English

Publication Type: Journal article

Publication year: 2021

Journal

Nature Cell Biology Nature Research

Book Volume: 23

Pages Range: 796-807

Journal Issue: 7

DOI: 10.1038/s41556-021-00708-8

Abstract

Inflammatory bowel diseases present with elevated levels of intestinal epithelial cell (IEC) death, which compromises the gut barrier, activating immune cells and triggering more IEC death. The endogenous signals that prevent IEC death and break this vicious cycle, allowing resolution of intestinal inflammation, remain largely unknown. Here we show that prostaglandin E2 signalling via the E-type prostanoid receptor 4 (EP4) on IECs represses epithelial necroptosis and induces resolution of colitis. We found that EP4 expression correlates with an improved IBD outcome and that EP4 activation induces a transcriptional signature consistent with resolution of intestinal inflammation. We further show that dysregulated necroptosis prevents resolution, and EP4 agonism suppresses necroptosis in human and mouse IECs. Mechanistically, EP4 signalling on IECs converges on receptor-interacting protein kinase 1 to suppress tumour necrosis factor-induced activation and membrane translocation of the necroptosis effector mixed-lineage kinase domain-like pseudokinase. In summary, our study indicates that EP4 promotes the resolution of colitis by suppressing IEC necroptosis.

Authors with CRIS profile

Jay Patankar Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Fabrizio Mascia Medizinische Fakultät Kristina Koop Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Claudia Günther Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Stefan Wirtz Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Clemens Neufert Medizinische Fakultät Sebastian Zundler Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Markus Neurath Lehrstuhl für Innere Medizin I Christoph Becker Professur für Molekulare Gastroenterologie

Additional Organisation(s)

Interdisziplinäres Zentrum für Klinische Forschung

Related research project(s)

A076: Elucidating the regulation and function of Gasdermin C in intestinal infection and inflammation Feb. 1, 2020 - Jan. 31, 2023

Involved external institutions

University of British Columbia CA Canada (CA) Humboldt-Universität zu Berlin DE Germany (DE) Simon Fraser University CA Canada (CA) Northeast Agricultural University CN China (CN) University of Paris 7 - Denis Diderot / Université Paris VII Denis Diderot FR France (FR) adMare Bioinnovations CA Canada (CA)

How to cite

APA:

Patankar, J., Muller, T.M., Kantham, S., Acera, M.G., Mascia, F., Scheibe, K.,... Becker, C. (2021). E-type prostanoid receptor 4 drives resolution of intestinal inflammation by blocking epithelial necroptosis. Nature Cell Biology, 23(7), 796-807. https://doi.org/10.1038/s41556-021-00708-8

MLA:

Patankar, Jay, et al. "E-type prostanoid receptor 4 drives resolution of intestinal inflammation by blocking epithelial necroptosis." Nature Cell Biology 23.7 (2021): 796-807.

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