1. E-type prostanoid receptor 4 drives resolution of intestinal inflammation by blocking epithelial necroptosis
- Author
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Claudia Günther, Mano Mathew, Sebastian Zundler, Anja A. Kühl, Markus F. Neurath, Christina Heichler, Miguel Gonzalez Acera, Jay Paquette, Moritz Leppkes, Kevan Jacobson, Fabrizio Mascia, Stefan Wirtz, Jay V. Patankar, Yuqiang Yu, Christoph Becker, Srinivas Kantham, Kristina Scheibe, Robert N. Young, Barbara Ruder, Tanja M. Müller, Mousumi Mahapatro, Clemens Neufert, Raja Atreya, and Wei Li
- Subjects
Colon ,medicine.medical_treatment ,Necroptosis ,Anti-Inflammatory Agents ,digestive system ,Dinoprostone ,parasitic diseases ,medicine ,Animals ,Humans ,Intestinal Mucosa ,Colitis ,Receptor ,Protein kinase A ,Mice, Knockout ,Effector ,Chemistry ,Kinase ,Dextran Sulfate ,Epithelial Cells ,Cell Biology ,MAP Kinase Kinase Kinases ,medicine.disease ,digestive system diseases ,Cell biology ,Mice, Inbred C57BL ,Organoids ,Disease Models, Animal ,Receptor-Interacting Protein Serine-Threonine Kinases ,lipids (amino acids, peptides, and proteins) ,Signal transduction ,HT29 Cells ,Protein Kinases ,Receptors, Prostaglandin E, EP4 Subtype ,Signal Transduction ,Prostaglandin E - 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.
- Published
- 2021