Analysis of oxidative stress-induced Keap1/Nrf2 signaling in Treg cells. Implications for inflammatory bowel diseases?
Final Report Abstract
The aim of the present DFG grant was to analyze how oxidative stress mediated Nrf2 signaling impacts regulatory T (Treg) cells and their function in inflammatory and autoimmune diseases. Influencing redox metabolism of T cells is a promising therapeutic option instead of an unspecific suppression of the immune system. A tight modulation of inflammation while preserving the cells’ overall functionality would be much more desirable for the treatment of autoimmune and inflammatory diseases. Difficulties during the project were side effects due to unspecific CRE recombinase expression in the Foxp3creKeapfl/fl mouse model. We therefore performed most of the mouse studies in parallel with mixed bone-marrow chimeras or other conditional mouse models. The herein performed murine studies showed that Nrf2 activation intrinsically in Tregs contributes to a loss of Treg cells and diminished peripheral tolerance. We could furthermore show that NRF2 is downregulated in Treg cells and T cells in human chronic inflammatory conditions like in inflamed joints of JIA patients. In human T cells, activation of NRF2 had anti-inflammatory effects. Therefore, a therapeutic control of NRF2 activity might be a starting point to influence redox metabolism in T cells, but in-depth analysis of pathways and possible side-effects is necessary. We discussed the controversial findings of Nrf2 and ROS in T cells in autoimmune diseases in a Review in Frontiers in Immunology. Our work during this project also included breeding of new mouse lines (CD4CreERT2Nrf2fl/fl, FOXP3GFPNrf2-/-) and the establishment of new methods for human cells (transfection of primary T cells, sorting of human Tregs, cooperation and first experiments to perform metabolic flux analysis) and thus provides a very solid base to uncover roles of Nrf2 in Tregs and to pave the way for therapeutic interventions.
Publications
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Nrf2 expression driven by Foxp3 specific deletion of Keap1 results in loss of immune tolerance in mice. Eur J Immunol. 2020 Apr;50(4):515-524
Klemm P, Rajendiran A, Fragoulis A, Wruck C, Schippers A, Wagner N, Bopp T, Tenbrock K, Ohl K
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Oxidative Stress in SLE T Cells, Is NRF2 Really the Target to Treat? Front Immunol. 2021 Apr 23;12:633845
Ohl K, Tenbrock K.
