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

Fengge Wang; Meng Liu; Dan Ma; Zecheng Cai; Lei Liu; Juncheng Wang; Wenjie Zhang; Lin Zhao; Chengfeng Zhai; Yuekang Xu

doi:10.1016/j.intimp.2023.109758

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

Int Immunopharmacol. 2023 Mar:116:109758. doi: 10.1016/j.intimp.2023.109758. Epub 2023 Jan 26.

Authors

Fengge Wang¹, Meng Liu², Dan Ma², Zecheng Cai², Lei Liu², Juncheng Wang², Wenjie Zhang², Lin Zhao², Chengfeng Zhai³, Yuekang Xu⁴

Affiliations

¹ Anhui Provincial Key Laboratory for Conservation and Exploitation of Biological Resources, School of Life Science, Anhui Normal University, Wuhu, Anhui 241000, China; Anhui Province Key Laboratory of Active Biological Macro-molecules, Anhui Provincial Engineering Research Center for Polysaccharide Drugs, Wannan Medical College, Wuhu, Anhui 241000, China.
² Anhui Provincial Key Laboratory for Conservation and Exploitation of Biological Resources, School of Life Science, Anhui Normal University, Wuhu, Anhui 241000, China.
³ Anhui Province Key Laboratory of Active Biological Macro-molecules, Anhui Provincial Engineering Research Center for Polysaccharide Drugs, Wannan Medical College, Wuhu, Anhui 241000, China.
⁴ Anhui Provincial Key Laboratory for Conservation and Exploitation of Biological Resources, School of Life Science, Anhui Normal University, Wuhu, Anhui 241000, China. Electronic address: yuekang.xu@hotmail.com.

PMID: 36706593
DOI: 10.1016/j.intimp.2023.109758

Abstract

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.

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

MeSH terms

Animals
Atherosclerosis* / drug therapy
Atherosclerosis* / metabolism
Dendritic Cells
Forkhead Transcription Factors / metabolism
Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism
Kynurenine* / metabolism
Mice
Receptors, Aryl Hydrocarbon / metabolism
T-Lymphocytes, Regulatory

Substances

Kynurenine
Receptors, Aryl Hydrocarbon
Indoleamine-Pyrrole 2,3,-Dioxygenase
Foxp3 protein, mouse
Forkhead Transcription Factors