Cell-specific Activation of the Nrf2 Antioxidant Pathway Increases Mucosal Inflammation in Acute but Not in Chronic Colitis.
OBJECTIVE
The transcription factor Nrf2 is a major modulator of the cellular antioxidant response. Oxidative burst of infiltrating macrophages leads to a massive production of reactive oxygen species in inflamed tissue of inflammatory bowel disease patients. This oxidative burst contributes to tissue destruction and epithelial permeability, but it is also an essential part of the antibacterial defence. We therefore investigated the impact of the Nrf2 orchestrated antioxidant response in both acute and chronic intestinal inflammation.


METHODS
To study the role of Nrf2 overexpression in mucosal inflammation, we used transgenic mice conditionally expressing a constitutively active form of Nrf2 [caNrf2] either in epithelial cells or in the myeloid cell lineage. Acute colitis was induced by dextran sulphate sodium [DSS] in transgenic and control animals, and changes in gene expression were evaluated by genome-wide expression studies. Long-term effects of Nrf2 activation were studied in mice with an IL-10-/- background.


RESULTS
Expression of caNrf2 either in epithelial cells or myeloid cells resulted in aggravation of DSS-induced acute colitis. Aggravation of inflammation by caNrf2 was not observed in the IL-10-/- model of spontaneous chronic colitis, where even a trend towards reduced prolapse rate was observed.


CONCLUSIONS
Our findings show that a well-balanced redox homeostasis is as important in epithelial cells as in myeloid cells during induction of colitis. Aggravation of acute DSS colitis in response to constitutive Nrf2 expression emphasises the importance of tight regulation of Nrf2 during the onset of intestinal inflammation.
Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.|Zurich Center for Integrative Human Physiology [ZIHP], University of Zurich, Zurich, Switzerland.
Alexandra
A
Gerstgrasser
Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
Hassan
H
Melhem
Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.|Zurich Center for Integrative Human Physiology [ZIHP], University of Zurich, Zurich, Switzerland.
Irina
I
Leonardi
Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
Kirstin
K
Atrott
Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
Matthias
M
Schäfer
Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
Sabine
S
Werner
Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.|Zurich Center for Integrative Human Physiology [ZIHP], University of Zurich, Zurich, Switzerland.
Gerhard
G
Rogler
Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.|Zurich Center for Integrative Human Physiology [ZIHP], University of Zurich, Zurich, Switzerland.
Isabelle
I
Frey-Wagner
D000208:Acute Disease; D000818:Animals; D002908:Chronic Disease; D003092:Colitis / Q000209:etiology* / Q000503:physiopathology; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D016753:Interleukin-10 / Q000502:physiology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000503:physiopathology; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000378:metabolism / Q000502:physiology; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D009195:Peroxidase / Q000378:metabolism; D016897:Respiratory Burst / Q000187:drug effects / Q000502:physiology
D016207:Cytokines; C556062:IL10 protein, mouse; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D016753:Interleukin-10; D016264:Dextran Sulfate; D009195:Peroxidase
Colitis; Nrf2; reactive oxygen species