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Article Dans Une Revue Nature Cell Biology Année : 2021

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

Tanja Müller
  • Fonction : Auteur
Srinivas Kantham
  • Fonction : Auteur
Miguel Gonzalez Acera
  • Fonction : Auteur
Fabrizio Mascia
  • Fonction : Auteur
Kristina Scheibe
  • Fonction : Auteur
Mousumi Mahapatro
  • Fonction : Auteur
Christina Heichler
  • Fonction : Auteur
Yuqiang Yu
  • Fonction : Auteur
Wei Li
Barbara Ruder
  • Fonction : Auteur
Moritz Leppkes
Mano Mathew
Stefan Wirtz
  • Fonction : Auteur
Anja Kühl
  • Fonction : Auteur
Jay Paquette
  • Fonction : Auteur
Raja Atreya
Sebastian Zundler
  • Fonction : Auteur
Markus Neurath
Robert Young
Christoph Becker

Résumé

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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Dates et versions

hal-04013948 , version 1 (03-03-2023)

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Citer

Jay Patankar, Tanja Müller, Srinivas Kantham, Miguel Gonzalez Acera, Fabrizio Mascia, et al.. E-type prostanoid receptor 4 drives resolution of intestinal inflammation by blocking epithelial necroptosis. Nature Cell Biology, 2021, 23 (7), pp.796-807. ⟨10.1038/s41556-021-00708-8⟩. ⟨hal-04013948⟩
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