Journal Article

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

Yu, Yuqiang, Ruder, Barbara, Mathew, Mano J., Wirtz, Stefan, Neufert, Clemens, Li, Wei, Günther, Claudia, Paquette, Jay, Zundler, Sebastian, Heichler, Christina, Young, Robert N., Becker, Christoph, Patankar, Jay V., Acera, Miguel Gonzalez, Scheibe, Kristina, Mascia, Fabrizio, Atreya, Raja, Kantham, Srinivas, Mahapatro, Mousumi, Neurath, Markus F., Kühl, Anja A., Müller, Tanja M., Leppkes, Moritz, Jacobson, Kevan

2021

Overview

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. Patankar et al. identify E-type prostanoid receptor 4 as a negative regulator of tumour necrosis factor signalling and mixed-lineage kinase domain-like pseudokinase activation, thereby suppressing necroptosis of intestinal epithelial cells and promoting resolution of intestinal inflammation.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/2 / 13/51 / 42/47 / 45/91 / 631/250/249/2510 / 631/250/256 / 631/80/82/2344 / 64/60 / Animals / Anti-Inflammatory Agents - pharmacology / Biomedical and Life Sciences / Cancer Research / Care and treatment / Cell Biology / Cell death / Cell receptors / Cellular signal transduction / Colitis / Colitis - chemically induced / Colitis - metabolism / Colitis - pathology / Colitis - prevention & control / Colon - drug effects / Colon - metabolism / Colon - pathology / Death / Development and progression / Developmental Biology / Dextran Sulfate / Dinoprostone - metabolism / Disease Models, Animal / Domains / Epithelial cells / Epithelial Cells - drug effects / Epithelial Cells - metabolism / Epithelial Cells - pathology / Epithelium / Health aspects / HT29 Cells / Humans / Immune system / Inflammation / Inflammatory bowel disease / Inflammatory bowel diseases / Intestinal Mucosa - drug effects / Intestinal Mucosa - metabolism / Intestinal Mucosa - pathology / Intestine / Kinases / Life Sciences / MAP kinase / MAP Kinase Kinase Kinases - genetics / MAP Kinase Kinase Kinases - metabolism / Medical research / Medicine, Experimental / Mice / Mice, Inbred C57BL / Mice, Knockout / Mortality / Necroptosis / Necroptosis - drug effects / Necrosis / Organoids / Prostaglandin E2 / Prostaglandins E / Protein kinase / Protein Kinases - genetics / Protein Kinases - metabolism / Receptor-Interacting Protein Serine-Threonine Kinases - genetics / Receptor-Interacting Protein Serine-Threonine Kinases - metabolism / Receptors / Receptors, Prostaglandin E, EP4 Subtype - agonists / Receptors, Prostaglandin E, EP4 Subtype - genetics / Receptors, Prostaglandin E, EP4 Subtype - metabolism / Signal Transduction / Signaling / Stem Cells / Transcription activation / Translocation / Tumor necrosis factor / Tumor necrosis factor-TNF / Tumors