REDOX-mediated modulation of immune stimulation by Toll-like receptors (TLR)

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Activation of macrophages and dendritic cells (DC) by triggering Toll-like receptors (TLR) like TLR4 induces oxygen radicals (ROS) that are toxic for bacteria. Simultaneously, ligands that trigger TLR4 on macrophages or dendritic cells (DC) induce an IL-12 and IL-23 producing, pro-inflammatory phenotype (DC1). While acute ROS stress has bactericidal effects, prolonged ROS stress deviates IL-12 and IL-23 producing DC1 into a DC2 phenotype. Such DC2 produce IL-10 instead of IL-12 or IL-23 when stimulated via the TLR4 receptor. Simultaneously, prolonged ROS stress suppresses the development of Th1/Th17 cells and of Th1/Th17-induced diseases like psoriasis or multiple sclerosis, and their model diseases in mice. As ROS and of ROS scavengers have such a key impact on the immune system, we will analyze their effect on the differentiation and development of DC and on the development of cellular immune responses, using various mouse lines with distinct genetic alterations in the ROS metabolism. Here we will focus on glutathione/glutamate transporter-fl/fl-CreERT2 and fl/fl-Rosa xCT-knock-in-CreERT2 mice, where we can use tamoxifen to analyze the endogenous ROS regulation in distinct cell populations. Initiated by our recently published data, we will focus on the endogenous REDOX regulation in DC. As relatively simple small molecules regulate ROS stress in humans in vivo and are already available for therapeutic purposes, the data will provide important insights into the natural course of infectious and autoimmune diseases and their therapy by immunotherapies.