Caspase-8 regulates TNF-α-induced epithelial necroptosis and terminal ileitis.
Caspase-8 regulates TNF-α-induced epithelial necroptosis and terminal ileitis.
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DOI：
10.1038/nature10400
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发表时间：
2011-09-14
期刊：
影响因子：
64.8
通讯作者：
Becker, Christoph
中科院分区：
文献类型：
--
作者：
Guenther, Claudia;Martini, Eva;Wittkopf, Nadine;Amann, Kerstin;Weigmann, Benno;Neumann, Helmut;Waldner, Maximilian J.;Hedrick, Stephen M.;Tenzer, Stefan;Neurath, Markus F.;Becker, Christoph
肠上皮功能障碍被认为导致共生细菌过度移位到肠壁，从而导致克罗恩病的慢性粘膜炎症；人类的一种不可治愈的炎症性肠病，其特征是末端回肠发炎。除了细胞紧密接触所建立的物理屏障外，特殊的上皮细胞，如潘氏细胞和杯状细胞，通过分泌粘液和抗菌肽来提供先天免疫防御功能，这些粘液和抗菌肽阻碍了邻近上皮的细菌的访问和生存。上皮细胞死亡是肠道炎症的一个标志，并被认为是导致人类克罗恩病(CD)的致病机制。然而，上皮细胞死亡的调节及其在肠道内稳态中的作用仍然知之甚少。在这里，我们展示了caspase-8在调节肠上皮细胞坏死性下垂(IEC)和终末期回肠炎中的关键作用。肠上皮caspase-8基因有条件缺失的小鼠(Casp8ΔIEC)会自发地在回肠末端发生炎性病变，并极易患结肠炎。Casp8ΔIEC小鼠缺乏潘氏细胞，杯状细胞数量减少，提示肠道上皮细胞抗微生物免疫细胞功能失调。Casp8ΔIEC小鼠小肠隐窝潘氏细胞区细胞死亡增加。肿瘤坏死因子-α诱导的上皮细胞死亡与受体相互作用蛋白3的表达增加有关，阻断坏死性下垂可抑制细胞死亡。最后，我们在人类Paneth细胞中发现了高水平的RIP3，并在克罗恩病患者的回肠末端增加了坏死性下垂，这表明坏死性下垂在该疾病的发病机制中可能起到了作用。综上所述，我们的数据显示了caspase-8在调节肠道内环境平衡和保护肠内皮细胞免受肿瘤坏死因子-α诱导的坏死性细胞死亡中的重要作用。
Dysfunction of the intestinal epithelium is believed to result in excessive translocation of commensal bacteria into the bowel wall that drives chronic mucosal inflammation in Crohn's disease; an incurable inflammatory bowel disease in humans characterized by inflammation of the terminal ileum. Beside the physical barrier established by the tight contact of cells, specialized epithelial cells such as Paneth cells and goblet cells provide innate immune defence functions by secreting mucus and antimicrobial peptides which hamper access and survival of bacteria adjacent to the epithelium. Epithelial cell death is a hallmark of intestinal inflammation and has been discussed as a pathogenic mechanism driving Crohn's disease (CD) in humans. However, the regulation of epithelial cell death and its role in intestinal homeostasis remains poorly understood. Here we demonstrate a critical role for caspase-8 in regulating necroptosis of intestinal epithelial cells (IEC) and terminal ileitis. Mice with a conditional deletion of caspase-8 in the intestinal epithelium (Casp8ΔIEC) spontaneously developed inflammatory lesions in the terminal ileum and were highly susceptible to colitis. Casp8ΔIEC mice lacked Paneth cells and showed reduced numbers of goblet cells suggesting dysregulated anti-microbial immune cell functions of the intestinal epithelium. Casp8ΔIEC mice showed increased cell death in the Paneth cell area of small intestinal crypts. Epithelial cell death was induced by tumor necrosis factor (TNF) -α, was associated with increased expression of receptor-interacting protein 3 (RIP3) and could be inhibited upon blockade of necroptosis. Finally, we identified high levels of RIP3 in human Paneth cells and increased necroptosis in the terminal ileum of patients with Crohn's disease, suggesting a potential role of necroptosis in the pathogenesis of this disease. Taken together, our data demonstrate a critical function of caspase-8 in regulating intestinal homeostasis and in protecting IEC from TNF-α induced necroptotic cell death.
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