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Epithelial NEMO links innate immunity to chronic intestinal inflammation

Arianna Nenci, Christoph Becker, Andy Wullaert UGent, Ralph Gareus, Geert van Loo UGent, Silvio Danese, Marion Huth, Alexei Nikolaev, Clemens Neufert, Blair Madison, et al. (2007) NATURE. 446(7135). p.557-561
abstract
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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
COLON-CANCER, PROGRESSION, BOWEL-DISEASE, CANCER DEVELOPMENT, INCONTINENTIA PIGMENTI, GAMMA-DEFICIENT MICE, NF-KAPPA-B, ACTIVATION, DELETION, COLITIS
journal title
NATURE
Nature
volume
446
issue
7135
pages
557 - 561
Web of Science type
Article
Web of Science id
000245242900053
JCR category
MULTIDISCIPLINARY SCIENCES
JCR impact factor
28.751 (2007)
JCR rank
1/47 (2007)
JCR quartile
1 (2007)
ISSN
0028-0836
DOI
10.1038/nature05698
language
English
UGent publication?
no
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
1202538
handle
http://hdl.handle.net/1854/LU-1202538
date created
2011-04-05 13:16:07
date last changed
2016-12-19 15:38:07
@article{1202538,
  abstract     = {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.},
  author       = {Nenci, Arianna and Becker, Christoph and Wullaert, Andy and Gareus, Ralph and van Loo, Geert and Danese, Silvio and Huth, Marion and Nikolaev, Alexei and Neufert, Clemens and Madison, Blair and Gumucio, Deborah and Neurath, Markus F and Pasparakis, Manolis},
  issn         = {0028-0836},
  journal      = {NATURE},
  keyword      = {COLON-CANCER,PROGRESSION,BOWEL-DISEASE,CANCER DEVELOPMENT,INCONTINENTIA PIGMENTI,GAMMA-DEFICIENT MICE,NF-KAPPA-B,ACTIVATION,DELETION,COLITIS},
  language     = {eng},
  number       = {7135},
  pages        = {557--561},
  title        = {Epithelial NEMO links innate immunity to chronic intestinal inflammation},
  url          = {http://dx.doi.org/10.1038/nature05698},
  volume       = {446},
  year         = {2007},
}

Chicago
Nenci, Arianna, Christoph Becker, Andy Wullaert, Ralph Gareus, Geert van Loo, Silvio Danese, Marion Huth, et al. 2007. “Epithelial NEMO Links Innate Immunity to Chronic Intestinal Inflammation.” Nature 446 (7135): 557–561.
APA
Nenci, A., Becker, C., Wullaert, A., Gareus, R., van Loo, G., Danese, S., Huth, M., et al. (2007). Epithelial NEMO links innate immunity to chronic intestinal inflammation. NATURE, 446(7135), 557–561.
Vancouver
1.
Nenci A, Becker C, Wullaert A, Gareus R, van Loo G, Danese S, et al. Epithelial NEMO links innate immunity to chronic intestinal inflammation. NATURE. 2007;446(7135):557–61.
MLA
Nenci, Arianna, Christoph Becker, Andy Wullaert, et al. “Epithelial NEMO Links Innate Immunity to Chronic Intestinal Inflammation.” NATURE 446.7135 (2007): 557–561. Print.