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Epithelial NEMO links innate immunity to chronic intestinal inflammation

Abstract

Deregulation of intestinal immune responses seems to have a principal function in the pathogenesis of inflammatory bowel disease1,2,3,4. 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 peptides3,5,6. However, the molecular mechanisms that control this function of gut epithelial cells are poorly understood. Here we show that the transcription factor NF-κB, a master regulator of pro-inflammatory responses7,8, 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-κB through conditional ablation of NEMO (also called IκB kinase-γ (IKKγ)) or both IKK1 (IKKα) and IKK2 (IKKβ)—IKK subunits essential for NF-κB activation7,8,9—spontaneously caused severe chronic intestinal inflammation in mice. NF-κB 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-κB signalling defect in intestinal epithelial cells disrupts immune homeostasis in the gastrointestinal tract, causing an inflammatory-bowel-disease-like phenotype. Our results identify NF-κB 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.

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Figure 1: Intestinal epithelium-specific NEMO ablation causes severe spontaneous colitis.
Figure 2: Inflammation in the colon of NEMO IEC-KO mice.
Figure 3: Compromised epithelial integrity and bacterial translocation in the colon of NEMO IEC-KO mice.
Figure 4: NF-κB inhibition in intestinal epithelial cells causes inflammatory colitis that depends on TNFRI and MyD88 signalling. a,
Figure 5: NEMO-mediated NF-κB activation in intestinal epithelial cells is essential for the maintenance of epithelial barrier integrity and immune homeostasis in the colon.

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Acknowledgements

We thank K. Pfeffer and S. Akira for providing TNFRI-deficient and MyD88-deficient mice, respectively. This work was supported by grants from the German Research Council to C.B. and M.F.N., and by EU-FP6 grants MUGEN and IMDEMI to M.P.; A.W. received a research fellowship from the Alexander von Humboldt Foundation.

Author Contributions A. Nenci, C.B., A.W., R.G, G.v.L, M.F.N and M.P. designed the research. A. Nenci, C.B, A.W, R.G, G.v.L, S.D., M.H., A. Nikolaev and C.N. performed the research. B.M. and D.G. contributed new reagents. A. Nenci, C.B., A.W., R.G, M.F.N and M.P. analysed the data and wrote the paper. M.F.N. and M.P share senior authorship.

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Correspondence to Manolis Pasparakis.

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Nenci, A., Becker, C., Wullaert, A. et al. Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 446, 557–561 (2007). https://doi.org/10.1038/nature05698

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