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

通过触发Toll样受体（TLR）如TLR 4激活巨噬细胞和树突状细胞（DC）诱导对细菌有毒的氧自由基（ROS）。同时，触发巨噬细胞或树突状细胞（DC）上的TLR 4的配体诱导产生IL-12和IL-23的促炎表型（DC 1）。虽然急性ROS应激具有杀菌作用，但延长的ROS应激使产生IL-12和IL-23的DC 1偏离为DC 2表型。当通过TLR 4受体刺激时，这种DC 2产生IL-10而不是IL-12或IL-23。同时，长时间的ROS应激抑制Th 1/Th 17细胞和Th 1/Th 17诱导的疾病如银屑病或多发性硬化症及其小鼠模型疾病的发展。由于ROS和ROS清除剂对免疫系统具有如此关键的影响，我们将使用ROS代谢中具有不同遗传改变的各种小鼠品系来分析它们对DC的分化和发育以及对细胞免疫应答的发展的影响。在这里，我们将专注于谷胱甘肽/谷氨酸转运蛋白-fl/fl-CreERT 2和fl/fl-Rosa xCT-knock-in-CreERT 2小鼠，在那里我们可以使用他莫昔芬来分析不同细胞群体中的内源性ROS调节。由我们最近发表的数据开始，我们将专注于DC的内源性REDOX调节。由于相对简单的小分子在体内调节人类的ROS应激，并且已经可用于治疗目的，因此这些数据将为感染性和自身免疫性疾病的自然过程及其免疫疗法提供重要的见解。

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.