2. Academic Validation
  3. E-type prostanoid receptor 4 drives resolution of intestinal inflammation by blocking epithelial necroptosis

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

  • Nat Cell Biol. 2021 Jul;23(7):796-807. doi: 10.1038/s41556-021-00708-8.
Jay V Patankar 1 2,  Tanja M Müller 1 2,  Srinivas Kantham 3,  Miguel Gonzalez Acera 1 2,  Fabrizio Mascia 1 2,  Kristina Scheibe 1 2,  Mousumi Mahapatro 1 2,  Christina Heichler 1 2,  Yuqiang Yu 1 2,  Wei Li 4,  Barbara Ruder 1 2,  Claudia Günther 1 2,  Moritz Leppkes 1 2,  Mano J Mathew 5 6,  Stefan Wirtz 1 2,  Clemens Neufert 1 2,  Anja A Kühl 7 8,  Jay Paquette 9 10,  Kevan Jacobson 11,  Raja Atreya 2,  Sebastian Zundler 1 2,  Markus F Neurath 1 2,  Robert N Young 3,  Christoph Becker 12 13
Affiliations

Affiliations

  • 1 Department of Medicine 1, University of Erlangen-Nuremberg, Erlangen, Germany.
  • 2 Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany.
  • 3 Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
  • 4 College of Veterinary Medicine, Northeast Agricultural University, Harbin, People's Republic of China.
  • 5 INSERM, Cordeliers Research Centre, Sorbonne Paris Cité, Université Paris Descartes, Université Paris Diderot, Paris, France.
  • 6 Allianstic Research Laboratory, EFREI Paris, Villejuif, France.
  • 7 Charité - Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Medizinische Klinik für Gastroenterologie, Infektiologie und Rheumatologie, Berlin, Germany.
  • 8 Charité - Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt Universität zu Berlin and Berlin Institute of Health, iPATH.Berlin, Berlin, Germany.
  • 9 Centre for Drug Research and Development, Vancouver, BC, Canada.
  • 10 adMare BioInnovations, Vancouver, British Columbia, Canada.
  • 11 Department of Pediatrics, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada.
  • 12 Department of Medicine 1, University of Erlangen-Nuremberg, Erlangen, Germany. [email protected].
  • 13 Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany. [email protected].
PMID: 34239062 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.

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