Department of Medicine 1, Friedrich-Alexander-University, D-91054 Erlangen, Germany.
Nature. 2011 Sep 14;477(7364):335-9. doi: 10.1038/nature10400.
Dysfunction of the intestinal epithelium is believed to result in the 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. In healthy individuals, the intestinal epithelium maintains a physical barrier, established by the tight contact of cells. Moreover, 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 possible pathogenic mechanism driving Crohn's disease in humans. However, the regulation of epithelial cell death and its role in intestinal homeostasis remain poorly understood. Here we demonstrate a critical role for caspase-8 in regulating necroptosis of intestinal epithelial cells (IECs) and terminal ileitis. Mice with a conditional deletion of caspase-8 in the intestinal epithelium (Casp8(ΔIEC)) spontaneously developed inflammatory lesions in the terminal ileum and were highly susceptible to colitis. Casp8(ΔIEC) mice lacked Paneth cells and showed reduced numbers of goblet cells, indicating dysregulated antimicrobial immune cell functions of the intestinal epithelium. Casp8(ΔIEC) mice showed increased cell death in the Paneth cell area of small intestinal crypts. Epithelial cell death was induced by tumour necrosis factor (TNF)-α, was associated with increased expression of receptor-interacting protein 3 (Rip3; also known as Ripk3) and could be inhibited on blockade of necroptosis. Lastly, 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. Together, our data demonstrate a critical function of caspase-8 in regulating intestinal homeostasis and in protecting IECs from TNF-α-induced necroptotic cell death.
肠上皮功能障碍被认为会导致共生菌过度易位到肠壁，从而驱动克罗恩病（一种无法治愈的人类炎症性肠病，其特征是末端回肠炎的炎症）的慢性黏膜炎症。在健康个体中，肠上皮通过细胞的紧密接触维持物理屏障。此外，特殊的上皮细胞，如潘氏细胞和杯状细胞，通过分泌黏液和抗菌肽提供先天免疫防御功能，从而阻碍上皮附近细菌的进入和存活。上皮细胞死亡是肠道炎症的一个标志，并被认为是驱动人类克罗恩病的一种可能的发病机制。然而，上皮细胞死亡的调节及其在肠道稳态中的作用仍知之甚少。在这里，我们证明了半胱天冬酶-8 在调节肠上皮细胞 (IEC) 的坏死性凋亡和末端回肠炎中起着关键作用。在肠上皮细胞中条件性缺失半胱天冬酶-8 的小鼠（Casp8(ΔIEC)）在末端回肠中自发形成炎症性病变，并且对结肠炎高度易感。Casp8(ΔIEC) 小鼠缺乏潘氏细胞，并且杯状细胞数量减少，表明肠道上皮的抗菌免疫细胞功能失调。Casp8(ΔIEC) 小鼠在小肠隐窝的潘氏细胞区域显示出增加的细胞死亡。上皮细胞死亡由肿瘤坏死因子 (TNF)-α 诱导，与受体相互作用蛋白 3 (Rip3；也称为 Ripk3) 的表达增加有关，并且可以通过阻断坏死性凋亡来抑制。最后，我们在人类潘氏细胞中发现了高水平的 RIP3，并在克罗恩病患者的末端回肠中发现了增加的坏死性凋亡，这表明坏死性凋亡在这种疾病的发病机制中可能具有潜在作用。总之，我们的数据表明半胱天冬酶-8 在调节肠道稳态和保护 IEC 免受 TNF-α 诱导的坏死性凋亡细胞死亡方面具有关键作用。
