Header

UZH-Logo

Maintenance Infos

Cell-specific activation of the nrf2 antioxidant pathway increases mucosal inflammation in acute but not in chronic colitis


Gerstgrasser, Alexandra; Melhem, Hassan; Leonardi, Irina; Atrott, Kirstin; Schäfer, Matthias; Werner, Sabine; Rogler, Gerhard; Frey-Wagner, Isabelle (2017). Cell-specific activation of the nrf2 antioxidant pathway increases mucosal inflammation in acute but not in chronic colitis. Journal of Crohn's & colitis, 11(4):485-499.

Abstract

BACKGROUND AND AIMS 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.

Abstract

BACKGROUND AND AIMS 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.

Statistics

Altmetrics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Center for Integrative Human Physiology
04 Faculty of Medicine > University Hospital Zurich > Clinic for Gastroenterology and Hepatology
Dewey Decimal Classification:610 Medicine & health
Language:German
Date:1 April 2017
Deposited On:13 Feb 2017 13:42
Last Modified:18 Apr 2017 01:03
Publisher:Oxford University Press
ISSN:1873-9946
Publisher DOI:https://doi.org/10.1093/ecco-jcc/jjw172
PubMed ID:27683801

Download

Full text not available from this repository.
View at publisher