Analysis of oxidative stress-induced Keap1/Nrf2 signaling in Treg cells. Implications for inflammatory bowel diseases?

• Applicant: Dr. Kim Karena Ohl
• Subject Area: Pediatric and Adolescent Medicine
• Term: from 2017 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 389351483

The incidence of inflammatory bowel diseases (IBD) is rising. Chronic intestinal inflammation results in severe morbidity that sometimes requires life-long immunosuppression and severely impairs the quality of life of children and adults. Oxidative stress within the intestinal epithelium is thought to play a key role in the pathogenesis of intestinal inflammation. However, the effects of oxidative stress on immune cells are unknown. Regulatory T cells (Tregs) play a major role in intestinal homeostasis and accumulate in inflamed mucosa in IBD but fail to suppress inflammation. We aim to study how oxidative stress influences Tregs by analyzing the key transcription factor of the oxidative stress response - Nrf2. Mice bearing a constitutive activation of Nrf2 in Treg cells (Foxp3creKeapfl/fl mice) accumulate high percentages of Foxp3 expressing Treg cells in spleen and lymph nodes but reveal surprising signs of autoimmune inflammation such as lymphadenopathy and myocarditis. In addition to this, Nrf2 is overexpressed in Treg cells in peripheral blood and inflamed mucosa in IBD patients. We hypothesize that oxidative stress-mediated Nrf2 signaling critically regulates Treg cells and may contribute to their dysregulations in IBD. To this end we will first analyze how Tregs with constitutive Nrf2 activation influence immune tolerance by in-depth analysis of Foxp3creKeapfl/fl mice and cell transfer experiments. We will then analyze the underlying mechanism by the use of microarray analysis and functional assays. Finally, we will test the relevance by analyzing how oxidative stress/Nrf2 signaling influences Tregs in human IBD.Our approach will define the role of Nrf2 signaling pathways in Tregs and may have implications for diseases associated with oxidative stress and dysregulated Treg responses.

• DFG Programme: Research Grants