Nrf2-Deficient Mice Have an Increased Susceptibility to Dextran Sulfate Sodium–Induced Colitis

Abstract

Inflammatory bowel diseases, chronic inflammatory disorders, have been strongly linked with an increased risk of the development of colorectal cancer. Understanding the etiology of these diseases is pivotal for the improvement of currently available strategies to fight against inflammatory bowel disease, and more importantly, to prevent colorectal cancer. Nuclear factor-erythroid 2-related factor 2 (Nrf2) has been known to be a transcriptional factor which plays a crucial role in cytoprotection against inflammation, as well as oxidative and electrophilic stresses. The aim of this study is to investigate the role of Nrf2 in the regulation of dextran sulfate sodium (DSS)-induced experimental colitis in mice. Nrf2-deficient mice were found to be more susceptible to DSS-induced colitis as shown by the increased severity of colitis following 1 week of oral administration of 1% DSS. The increased severity of colitis in Nrf2(À/À) mice was found to be associated with decreased expression of antioxidant/phase II detoxifying enzymes including heme-oxygenase-1, NAD(P)H-quinone reductase-1, UDP-glucurosyltransferase 1A1, and glutathione S-transferase Mu-1. In addition, proinflammatory mediators/cytokines such as COX-2, inducible nitric oxide, interleukin 1B, interleukin 6, and tumor necrosis factor A were significantly increased in the colonic tissues of Nrf2(À/À) mice compared with their wild-type (Nrf2+/+) counterparts. In summary, we show for the first time that mice lacking Nrf2 are more susceptible to DSS-induced colitis. Our data suggests that Nrf2 could play an important role in protecting intestinal integrity, through regulation of proinflammatory cytokines and induction of phase II detoxifying enzymes.

Sulforaphane Attenuates Muscle Inflammation in Dystrophin-deficient mdx Mice via NF-E2-related Factor 2 (Nrf2)-mediated Inhibition of NF-κB Signaling Pathway

“…Recent research indicates that Nrf2 plays a strong anti-inflammatory role in many different tissues via inhibition of the NF-B signaling pathway. Nrf2 plays a protective role in inflammationmediated colonic tumorigenesis (11), allergen-mediated airway inflammation (12), cigarette smoke-induced emphysema (13), and dextran sulfate sodium-mediated colitis (14). However, the role of Nrf2 in the inflammation of dystrophic muscles and whether Nrf2 may inhibit NF-B signaling pathway in patients with DMD are still unknown.…”

Increased colonic inflammatory injury and formation of aberrant crypt foci in Nrf2‐deficient mice upon dextran sulfate treatment

“…Nrf2-deficient lymphocytes displayed enhanced proliferation, relative to WT lymphocytes, after anti-CD3 stimulation, demonstrating a direct influence of Nrf2 genotype on the activity of cells important in the adaptive immune response. 18 Similarly, Khor et al 21 very recently demonstrated increased expression of proinflammatory cytokines in colons of N0 mice, relative to WT mice, in response to challenge with DSS. Collectively, these studies implicate an important role of Nrf2 in attenuating proinflammatory signaling and colonic inflammatory cell infiltration in response to inflammatory stimuli.…”

TRPM2-mediated Ca2+ influx induces chemokine production in monocytes that aggravates inflammatory neutrophil infiltration

“…Cumulative evidence supports that ROS may function as mediators for aggravation of symptoms and pathophysiological responses in ulcerative colitis 19,20 . In mice, deficiency of nuclear factor erythroid-2-related factor-2 (Nrf2), a redox-sensitive transcriptional factor that regulates antioxidant genes 36 , or an impaired superoxide dismutase activity 18 has been reported to increase susceptibility to DSS-induced colitis, indicating a major role of antioxidants in protecting the intestine against ROS in colitis. Notably, 100 μM H 2 O 2 induced cell death in only 20% of U937 cells 14 but induced submaximal activation of CXCL8 transcription (nearly 80% maximum; Supplementary Fig.…”