RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis.
RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis.
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DOI：
10.1038/nature13608
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发表时间：
2014-09-04
期刊：
影响因子：
64.8
通讯作者：
Pasparakis M
中科院分区：
文献类型：
--
作者：
Dannappel M;Vlantis K;Kumari S;Polykratis A;Kim C;Wachsmuth L;Eftychi C;Lin J;Corona T;Hermance N;Zelic M;Kirsch P;Basic M;Bleich A;Kelliher M;Pasparakis M
坏死性下垂是胚胎发育、组织动态平衡、免疫和炎症等过程中细胞程序性死亡的重要途径。RIPK1与炎症和细胞死亡信号有关，其激酶活性被认为是RIPK3介导的坏死性下垂的驱动因素。在这里，我们展示了RIPK1的激酶非依赖性支架功能，通过抑制上皮细胞凋亡和坏死性下垂来调节屏障组织中的动态平衡和预防炎症。肠上皮细胞(IEC)特异性RIPK1基因敲除可导致IEC凋亡、绒毛萎缩、杯状细胞和潘氏细胞丢失以及过早死亡。这种病理发展独立于微生物区系和MyD88信号，但部分地被TNFR1(也称为TNFRSF1A)缺乏所挽救。上皮FADD消融可抑制IEC的凋亡，并通过IEC特异性RIPK1基因敲除防止小鼠的过早死亡。然而，在IECS中同时缺乏RIPK1和FADD的小鼠出现了依赖RIPK3的IEC坏死性下垂、Paneth细胞丢失和结肠局灶性侵蚀性炎症病变。此外，RIPK1激酶失活敲入延缓了FADD缺乏引起的IECs或角质形成细胞的炎症反应，表明FADD缺陷的上皮细胞依赖RIPK3的坏死性下垂只需要部分RIPK1激酶活性。表皮特异性RIPK1基因敲除引发角质形成细胞凋亡和坏死性下垂，并导致严重的皮肤炎症，这可以通过RIPK3而不是FADD缺陷来预防。这些发现表明，RIPK1在体内抑制了RIPK3介导的角质形成细胞的坏死性下垂，并发现与细胞凋亡相比，坏死性下垂是更有效的炎症触发因素。因此，RIPK1是肠和皮肤上皮细胞存活、动态平衡和炎症的主要调节因子。
Necroptosis has emerged as an important pathway of programmed cell death in embryonic development, tissue homeostasis, immunity and inflammation. RIPK1 is implicated in inflammatory and cell death signalling and its kinase activity is believed to drive RIPK3-mediated necroptosis. Here we show that kinase-independent scaffolding RIPK1 functions regulate homeostasis and prevent inflammation in barrier tissues by inhibiting epithelial cell apoptosis and necroptosis. Intestinal epithelial cell (IEC)-specific RIPK1 knockout caused IEC apoptosis, villus atrophy, loss of goblet and Paneth cells and premature death in mice. This pathology developed independently of the microbiota and of MyD88 signalling but was partly rescued by TNFR1 (also known as TNFRSF1A) deficiency. Epithelial FADD ablation inhibited IEC apoptosis and prevented the premature death of mice with IEC-specific RIPK1 knockout. However, mice lacking both RIPK1 and FADD in IECs displayed RIPK3-dependent IEC necroptosis, Paneth cell loss and focal erosive inflammatory lesions in the colon. Moreover, a RIPK1 kinase inactive knock-in delayed but did not prevent inflammation caused by FADD deficiency in IECs or keratinocytes, showing that RIPK3-dependent necroptosis of FADD-deficient epithelial cells only partly requires RIPK1 kinase activity. Epidermis-specific RIPK1 knockout triggered keratinocyte apoptosis and necroptosis and caused severe skin inflammation that was prevented by RIPK3 but not FADD deficiency. These findings revealed that RIPK1 inhibits RIPK3-mediated necroptosis in keratinocytes in vivo and identified necroptosis as a more potent trigger of inflammation compared with apoptosis. Therefore, RIPK1 is a master regulator of epithelial cell survival, homeostasis and inflammation in the intestine and the skin.
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