Department of Medicine 1, University of Erlangen-Nuremberg, Erlangen, Germany.
Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany.
Nat Cell Biol. 2021 Jul;23(7):796-807. doi: 10.1038/s41556-021-00708-8. Epub 2021 Jul 8.
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.
炎症性肠病表现为肠道上皮细胞 (IEC) 死亡水平升高，这会损害肠道屏障，激活免疫细胞并引发更多的 IEC 死亡。防止 IEC 死亡并打破这种恶性循环的内源性信号，从而允许肠道炎症的消退，在很大程度上仍然未知。在这里，我们表明，前列腺素 E2 通过 IEC 上的 E 型前列腺素受体 4 (EP4) 发出信号，抑制上皮细胞坏死，并诱导结肠炎的消退。我们发现 EP4 表达与改善的 IBD 结果相关，并且 EP4 激活诱导与肠道炎症消退一致的转录特征。我们进一步表明，失调的坏死阻止了消退，并且 EP4 激动剂抑制了人和小鼠 IEC 中的坏死。从机制上讲，IEC 上的 EP4 信号传导集中在受体相互作用蛋白激酶 1 上，以抑制肿瘤坏死因子诱导的坏死效应物混合谱系激酶结构域样伪激酶的激活和膜易位。总之，我们的研究表明，EP4 通过抑制 IEC 坏死来促进结肠炎的消退。
