Nature子刊:EP4抑制肠上皮细胞坏死性凋亡,缓解肠道炎症
创作:耿六一 审核:aluba 07月20日
  • EP4表达与IBD患者的预后改善相关;
  • EP4活化可缓解结肠炎,诱导与肠道炎症缓解相关的转录组变化,抑制DSS诱导的非凋亡性细胞死亡;
  • EP4选择性激动剂可在RIPK3及MLKL介导的过度坏死性凋亡中起保护性作用;
  • 机制上,EP4活化通过降低RIPK1及MLKL的磷酸化,并减少MLKL的寡聚化及膜易位,从而抑制IEC的坏死性凋亡,并可与TNF下游的TGF-β活化激酶1 (TAK1)协同作用;
  • EP4选择性激动剂可抑制IBD患者来源的肠道隐窝类器官中的IEC坏死性凋亡。
主编推荐语
aluba
IBD表现为肠道上皮细胞(IEC)的死亡增加,导致肠道屏障受损并激活免疫细胞,从而驱动更多的IEC死亡。Nature Cell Biology上发表的一项最新研究,发现E型前列腺素受体4(EP4)的表达与IBD患者的预后改善相关。机制上,激活EP4可通过抑制RIPK1介导的IEC坏死性凋亡,从而缓解肠道炎症。
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Nature Cell Biology [IF:28.824]

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

E型前列腺素受体4通过阻断上皮坏死性凋亡促进肠道炎症的缓解

10.1038/s41556-021-00708-8

07-08, Article

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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.

First Authors:
Jay V Patankar

Correspondence Authors:
Christoph Becker

All Authors:
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 Atreya,Sebastian Zundler,Markus F Neurath,Robert N Young,Christoph Becker

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Nature Cell Biology期刊

Prostanoids put a brake on necroptosis in IBD

2021-07-08

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