Epithelial NEMO links innate immunity to chronic intestinal inflammation (original) (raw)
- Letter
- Published: 14 March 2007
- Christoph Becker3 na1,
- Andy Wullaert1,
- Ralph Gareus1,
- Geert van Loo2,
- Silvio Danese4,
- Marion Huth2,
- Alexei Nikolaev3,
- Clemens Neufert3,
- Blair Madison5,
- Deborah Gumucio5,
- Markus F. Neurath3 na1 &
- …
- Manolis Pasparakis1,2
Nature volume 446, pages 557–561 (2007)Cite this article
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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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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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Author notes
- Arianna Nenci, Christoph Becker and Markus F. Neurath: These authors contributed equally to this work.
Authors and Affiliations
- Institute for Genetics, University of Cologne, Zülpicher Strasse 47, 50674 Cologne, Germany,
Arianna Nenci, Andy Wullaert, Ralph Gareus & Manolis Pasparakis - EMBL Mouse Biology Unit, I-00016 Monterotondo, Italy,
Arianna Nenci, Geert van Loo, Marion Huth & Manolis Pasparakis - I. Department of Medicine, Laboratory of Clinical Immunology, University of Mainz, Obere Zahlbacher Strasse 63, 55131 Mainz, Germany,
Christoph Becker, Alexei Nikolaev, Clemens Neufert & Markus F. Neurath - Division of Gastroenterology, Istituto Clinico Humanitas-IRCCS in Gastroenterology, Viale Manzoni 56, 20089 Rozzano, Milan, Italy,
Silvio Danese - Department of Cell & Developmental Biology, Center for Organogenesis, The University of Michigan, Ann Arbor, Michigan 48109-0616, USA,
Blair Madison & Deborah Gumucio
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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
- Received: 08 December 2006
- Accepted: 23 February 2007
- Published: 14 March 2007
- Issue Date: 29 March 2007
- DOI: https://doi.org/10.1038/nature05698