Epithelial NEMO links innate immunity to chronic intestinal inflammation

Arianna Nenci, Christoph Becker, Andy Wullaert, Ralph Gareus, Geert van Loo, Silvio Danese, Marion Huth, Alexei Nikolaev, Clemens Neufert, Blair Madison, Deborah Gumucio, Markus F. Neurath and Manolis Pasparakis ()
Additional contact information
Arianna Nenci: Institute for Genetics, University of Cologne, Zülpicher Strasse 47, 50674 Cologne, Germany
Christoph Becker: Laboratory of Clinical Immunology, University of Mainz, Obere Zahlbacher Strasse 63, 55131 Mainz, Germany
Andy Wullaert: Institute for Genetics, University of Cologne, Zülpicher Strasse 47, 50674 Cologne, Germany
Ralph Gareus: Institute for Genetics, University of Cologne, Zülpicher Strasse 47, 50674 Cologne, Germany
Geert van Loo: EMBL Mouse Biology Unit, I-00016 Monterotondo, Italy
Silvio Danese: Istituto Clinico Humanitas-IRCCS in Gastroenterology, Viale Manzoni 56, 20089 Rozzano, Milan, Italy
Marion Huth: EMBL Mouse Biology Unit, I-00016 Monterotondo, Italy
Alexei Nikolaev: Laboratory of Clinical Immunology, University of Mainz, Obere Zahlbacher Strasse 63, 55131 Mainz, Germany
Clemens Neufert: Laboratory of Clinical Immunology, University of Mainz, Obere Zahlbacher Strasse 63, 55131 Mainz, Germany
Blair Madison: Center for Organogenesis, The University of Michigan, Ann Arbor, Michigan 48109-0616, USA
Deborah Gumucio: Center for Organogenesis, The University of Michigan, Ann Arbor, Michigan 48109-0616, USA
Markus F. Neurath: Laboratory of Clinical Immunology, University of Mainz, Obere Zahlbacher Strasse 63, 55131 Mainz, Germany
Manolis Pasparakis: Institute for Genetics, University of Cologne, Zülpicher Strasse 47, 50674 Cologne, Germany

Nature, 2007, vol. 446, issue 7135, 557-561

Abstract: 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.

Date: 2007
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DOI: 10.1038/nature05698

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