Epithelial NEMO links innate immunity to chronic intestinal inflammation
Epithelial NEMO links innate immunity to chronic intestinal inflammation
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DOI：
10.1038/nature05698
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发表时间：
2007-03-29
期刊：
影响因子：
64.8
通讯作者：
Pasparakis, Manolis
中科院分区：
文献类型：
--
作者：
Nenci, Arianna;Becker, Christoph;Pasparakis, Manolis
肠道免疫反应的失调似乎在炎症性肠病的发病机制中起主要作用(1-4)。肠道上皮在维持肠道免疫平衡中起着至关重要的作用--作为分隔肠道细菌和免疫细胞的物理屏障，并表达抗菌肽(3，5，6)。然而，控制肠道上皮细胞这一功能的分子机制却知之甚少。在这里，我们展示了转录因子NF-kappa B，促炎反应的主要调节因子(7，8)，在肠道上皮细胞中发挥功能，控制上皮完整性以及粘膜免疫系统和肠道微生物群之间的相互作用。肠上皮细胞特异性抑制核因子-kappa B通过条件消融Nemo(也称为I-kappa B激酶-伽马(IKK-Gamma))或同时去除IKK1(IKKα)和IKK2(IKKβ)-激活NF-kappa B所必需的IKK亚单位(7-9)-自发地在小鼠中引起严重的慢性肠炎。核因子-kappaB缺乏导致结肠上皮细胞凋亡，抗菌肽表达受损，细菌移位到粘膜内。同时，这种上皮缺陷在结肠中引发了慢性炎症反应，最初以先天性免疫细胞为主，但后来也涉及T淋巴细胞。编码接头蛋白MyD88的基因缺失阻止了肠道炎症的发展，表明肠道细菌激活Toll样受体在该小鼠模型的疾病发病机制中是必不可少的。此外，NEMO缺乏使上皮细胞对肿瘤坏死因子(TNF)诱导的细胞凋亡敏感，而肿瘤坏死因子受体-1失活则抑制肠道炎症，表明肿瘤坏死因子受体-1信号在疾病诱导中起关键作用。这些发现表明，肠上皮细胞中原发的核因子-kappaB信号缺陷破坏了胃肠道的免疫稳态，导致炎症性肠病样表型。我们的结果表明，肠上皮细胞中的核因子-kappa B信号是上皮完整性和肠道免疫稳态的关键调节因子，并对理解控制人类炎症性肠病发病的机制具有重要意义。
Deregulation of intestinal immune responses seems to have a principal function in the pathogenesis of inflammatory bowel disease(1-4). The gut epithelium is critically involved in the maintenance of intestinal immune homeostasis-acting as a physical barrier separating luminal bacteria and immune cells, and also expressing antimicrobial peptides(3,5,6). However, the molecular mechanisms that control this function of gut epithelial cells are poorly understood. Here we show that the transcription factor NF kappa B, a master regulator of pro-inflammatory responses(7,8), functions in gut epithelial cells to control epithelial integrity and the interaction between the mucosal immune system and gut microflora. Intestinal epithelial-cell-specific inhibition of NF-kappa B through conditional ablation of NEMO ( also called I kappa B kinase-gamma ( IKK gamma)) or both IKK1 ( IKK alpha) and IKK2 ( IKK beta)-IKK subunits essential for NF-kappa B activation(7-9)-spontaneously caused severe chronic intestinal inflammation in mice. NF-kappa B deficiency led to apoptosis of colonic epithelial cells, impaired expression of antimicrobial peptides and translocation of bacteria into the mucosa. Concurrently, this epithelial defect triggered a chronic inflammatory response in the colon, initially dominated by innate immune cells but later also involving T lymphocytes. Deficiency of the gene encoding the adaptor protein MyD88 prevented the development of intestinal inflammation, demonstrating that Toll-like receptor activation by intestinal bacteria is essential for disease pathogenesis in this mouse model. Furthermore, NEMO deficiency sensitized epithelial cells to tumour-necrosis factor ( TNF)-induced apoptosis, whereas TNF receptor-1 inactivation inhibited intestinal inflammation, demonstrating that TNF receptor-1 signalling is crucial for disease induction. These findings demonstrate that a primary NF-kappa B signalling defect in intestinal epithelial cells disrupts immune homeostasis in the gastrointestinal tract, causing an inflammatory-bowel-disease-like phenotype. Our results identify NF-kappa B signalling in the gut epithelium as a critical regulator of epithelial integrity and intestinal immune homeostasis, and have important implications for understanding the mechanisms controlling the pathogenesis of human inflammatory bowel disease.