Dendritic cell-expressed IDO alleviates atherosclerosis by expanding CD4+CD25+Foxp3+Tregs through IDO-Kyn-AHR axis

Atherosclerosis is a chronic inflammatory disease, in which immune disorders constitute an essential part of vascular pathogenesis. Accumulating evidence indicates that dendritic cells (DCs) and their tryptophan metabolisms regulate host immune responses. However, the mechanistic involvement of metabolic products from DCs in dysregulating vascular immunity during the development of atherosclerosis is far from clear. Flow cytometry examination showed immune cells were accumulated and gradually increased in the atherosclerotic lesions during the atherosclerosis progression, in which IDO⁺DCs were enriched. To study the role of DC-expressed IDO in the development of atherosclerosis, we made a stable IDO-overexpressing DC line (IDO^oeDCs) by lentiviral Infection for adoptive transfer into pro-atherosclerotic mice. Compared with DCs containing empty vector (Vector^CtrlDC)-treated group, treatment of IDO^oeDCs led to a significant reduction of atherosclerotic lesions in the aorta, with decreased aortic infiltration of Th1 immune cells and reduced vascular inflammation. Importantly, IDO^oeDCs increased aortic kynurenine (Kyn) concentration and Aryl Hydrocarbon Receptor (AHR) expression, concomitant with CD4⁺CD25⁺Foxp3⁺Treg expansion in the aortic tissues, which were abrogated by AHR antagonist treatment. These results indicate that DC-expressed IDO reduces atherosclerotic lesions by inducing aortic CD4⁺CD25⁺Foxp3⁺Treg expansion through IDO-Kyn-AHR axis, which may represent a novel possibility for treatment or prevention of atherosclerosis.

Aryl hydrocarbon receptor; Atherosclerosis; Dendritic cells; Indoleamine 2, 3-dioxygenase; Kynurenine; Regulatory T cells.