The role of the Aryl hydrocarbon receptor in antigen-presenting cells in atherosclerosis

动脉粥样硬化是心肌梗死和中风等缺血性疾病的主要原因，这些疾病共同构成世界范围内死亡的主要原因。它被认为是一种慢性血管壁炎症性疾病，涉及先天和获得性免疫机制。配体激活的转录因子芳香烃受体(AhR)除了具有生理配体的功能外，还可以作为异源感受器发挥作用，已被描述为促进动脉粥样硬化对有毒环境污染物的响应。然而，AHR在动脉粥样硬化中的生理作用及其细胞类型的特殊功能还没有被研究。在初步实验中，我们证明了AhR在动脉粥样硬化相关的CD11c+抗原呈递免疫细胞中高表达，并且CD11c+细胞AhR缺乏会增加小鼠的动脉粥样硬化，这与肿瘤坏死因子-α的产生增加有关。因此，我们假设，病变CD11c+APC中AhR的表达通过抑制肿瘤坏死因子α的表达，作为炎症细胞激活的守门人来限制动脉粥样硬化。在本项目中，我们将评估CD11c+细胞AhR在动脉粥样硬化不同阶段病变形成中的作用，并系统分析AhR如何影响动脉粥样硬化中CD11c+细胞的聚集及其基因表达。此外，我们将研究AhR调节CD11c+免疫细胞产生肿瘤坏死因子α的机制，并在这些细胞中特异性地靶向肿瘤坏死因子α，以评估其在动脉粥样硬化中的细胞类型特异性贡献。最后，我们还将用翻译的方法评估AhR在人类动脉粥样硬化中的表达和相关的效应分子。

Atherosclerosis is the main cause of ischemic diseases such as myocardial infarction and stroke, which together constitute the leading cause of mortality worldwide. Recognized as a chronic inflammatory disease of the vascular wall, it involves innate as well as adaptive immune mechanisms. The ligand-activated transcription factor aryl hydrocarbon receptor (AhR), which in addition to physiological ligands can function as a xenobiotic sensor, has been described to promote atherosclerosis in response to toxic environmental contaminants. The physiological role of Ahr and its cell-type specific functions in atherosclerosis, however, have not been investigated. In preliminary experiments we demonstrated that Ahr is highly expressed in a population of atherosclerosis-associated CD11c+ antigen-presenting immune cells and that Ahr deficiency in CD11c+ cells increases atherosclerosis in mice, which was associated with an increased tumor necrosis factor (TNF)-α production. We therefore hypothesize that Ahr expression in lesional CD11c+ APCs limits atherosclerosis by acting as a gatekeeper of inflammatory cell activation via inhibition of TNFα expression. In this project we will evaluate the role of Ahr in CD11c+ cells in lesion formation at different stages of atherosclerosis and perform a systematic analysis of how Ahr affects the accumulation of CD11c+ cells and their gene expression in atherosclerosis. Moreover, we will investigate the mechanisms underlying Ahr-mediated regulation of TNFα production in CD11c+ immune cells and target TNFα specifically in these cells to evaluate its cell-type specific contribution in atherosclerosis. Finally, we will also evaluate Ahr expression and associated effector molecules in human atherosclerosis in a translational approach.