The proatherosclerotic function of indoleamine 2, 3-dioxygenase 1 in the developmental stage of atherosclerosis

Abstract

The discrepancy of indoleamine 2, 3-dioxygenase 1 (IDO1) function in atherosclerosis has been noted. Compared to the protective effect of IDO1 against established atherogenesis, the role of IDO1 in the developmental process of atherosclerosis is still unclear. Here, the expression patterns and activities of IDO1 and its isoenzyme tryptophan 2,3-dioxygenase (TDO) in aortas and blood samples of patients with atherosclerosis were investigated. IDO1 and TDO were colocalized with CD3-positive lymphocytes and CD68-positive macrophages in atherosclerotic lesions. The expression and activity of IDO1 and TDO increased with the grade of the histological classification in early atherosclerosis (grade I, II), but the increase did not continue in advanced atherosclerosis (grade III). Treatment of THP-1 macrophages (THP-M) with oxidized low-density lipoprotein (oxLDL) induced the expression of IDO1 via the PI3K/Akt/NF-κB pathway, indicating the potential function of IDO1 in foam cells. Before and after treatment with oxLDL on THP-M, IFN-γ-induced IDO1 exhibited different degrees of promotion on foaming, inflammatory factor production and cell apoptosis. Finally, we found that the IDO1 inhibitor 1-methyl-tryptophan could elevate the high-density lipoprotein cholesterol level in serum and reduce the area of the aortic atherosclerotic lesions in high-fat diet-fed ApoE−/− mice. Our study indicated that IDO1 played a complicated and unfixed role in the entire process of atherogenesis, despite the atheroprotective role in established atherosclerosis. IDO1 also had proatherosclerotic functions in the developmental stages of atherosclerosis. Modulation of IDO1 could be a good method for alleviating atherosclerosis.

AncPhore: A versatile tool for anchor pharmacophore steered drug discovery with applications in discovery of new inhibitors targeting metallo-β-lactamases and indoleamine/tryptophan 2,3-dioxygenases

“…3 A). These enzymes are first and rate-limiting enzymes of the kynurenine pathway, and implicated in neurodegenerative diseases and tumoral immune resistance; in particular, IDO1 and TDO have been demonstrated as important targets for cancer immunotherapy 23 , 24 , 25 , 26 . Although a number of IDO1 and TDO inhibitors have been reported and several inhibitors are in preclinical development 26 , 27 , 28 , 29 , discovery of new inhibitor chemotypes is still desirable at present.…”

Blockade of Macrophage CD147 Protects Against Foam Cell Formation in Atherosclerosis

“…Our data show that the basal level of CD147 in BMDMs is relative low and boosted in foam cells ( Figure 2N ). However, the human monocyte THP-1 cell line is derived from patient with acute monocytic leukemia and can differentiate into macrophages upon PMA stimulation and form foam cells when treated with ox-LDL ( Liang et al, 2019 ). It is in monocytes that CD147 has a relative low basal level and in macrophages that CD147 shows a remarkable increase.…”

What is the prospect of indoleamine 2,3-dioxygenase 1 inhibition in cancer? Extrapolation from the past

“…However, the depletion of TRP is not always synchronized with accumulation of KYN in human cancers (Table 6). In fact, TRP depletion is more sensitive to disease condition than Kyn accumulation, not only in cancers, but also in other diseases such as Alzheimer's disease and atherosclerosis [112][113][114]. TRP deprivation is significantly correlated with clinical outcomes like the quality of life in CRC, survival in malignant melanoma and advanced disease stage in lung cancer [39][40][41] while the KYN generation has a prognostic significance in adult T-cell leukemia/lymphoma (ATL) [42].…”