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

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

Research output: Contribution to journalOriginal Articlepeer-review

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.

Original languageEnglish
Pages (from-to)796-807
Number of pages12
JournalNATURE CELL BIOLOGY
Volume23
Issue number7
DOIs
Publication statusPublished - Jul 2021
Externally publishedYes

Keywords

  • Animals
  • Anti-Inflammatory Agents/pharmacology
  • Colitis/chemically induced
  • Colon/drug effects
  • Dextran Sulfate
  • Dinoprostone/metabolism
  • Disease Models, Animal
  • Epithelial Cells/drug effects
  • HT29 Cells
  • Humans
  • Intestinal Mucosa/drug effects
  • MAP Kinase Kinase Kinases/genetics
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Necroptosis/drug effects
  • Organoids
  • Protein Kinases/genetics
  • Receptor-Interacting Protein Serine-Threonine Kinases/genetics
  • Receptors, Prostaglandin E, EP4 Subtype/agonists
  • Signal Transduction
  • Mice

Fingerprint

Dive into the research topics of 'E-type prostanoid receptor 4 drives resolution of intestinal inflammation by blocking epithelial necroptosis'. Together they form a unique fingerprint.

Cite this