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

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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.