Indoleamine 2,3-Dioxygenase Fine-Tunes Immune Homeostasis in Atherosclerosis and Colitis through Repression of Interleukin-10 Production

Abstract

Indoleamine 2,3-dioxygenase 1 (Ido1) is a rate-limiting enzyme that catalizes the degradation of tryptophan along the kynurenine pathway. Here, we show that Ido1 activity sustains an immunostimulatory potential through inhibition of interleukin (Il)10. In atherosclerosis, Ido1-dependent inhibition of Il10 translates into disease exacerbation. The resistance of Ido1-deficient mice to enhanced immune activation is broken in Ido1/Il10 double-deficient mice, which show exaggerated immune responses and develop severe spontaneous colitis. We demonstrate that Ido1 activity is required for the regulation of Il10 and that kynurenic acid (Kna), an Ido1-derived metabolite, is responsible for reduced Il10 production through activation of a cAMP-dependent pathway and inhibition of Erk1/2 phosphorylation. Resupplementation of Ido1-deficient mice with Kna limits Il10 expression and promotes atherosclerosis. In human atherosclerotic lesions, increased levels of Kna are associated with an unstable plaque phenotype, and its blood levels predict death and recurrent myocardial infarction in patients with coronary artery disease.

Adaptive Response of T and B Cells in Atherosclerosis

“…68,69 In experimental atherosclerosis, exogenous treatment with the tryptophan metabolite 3-hydroxyanthranilic acid substantially decreased plaque size, 70 whereas pharmacological inhibition or the knockdown of IDO increased arterial inflammation and atherosclerosis. 71,72 Although a controversial study recently suggested a deleterious role for this pathway in atherogenesis, 73 several other data support the notion that IDO-mediated tryptophan metabolism plays an essential role in the maintenance of immune homeostasis in the vascular wall 69 and has beneficial effects on lipoprotein metabolism.…”

Metabolites: messengers between the microbiota and the immune system

“…IDO1 activity was shown to inhibit IL-10, which, in a model of atherosclerosis, leads to ameliorated disease (Metghalchi et al 2015). Ido1 −/− mice showed blooming of Lactobacilli similar to mice on a tryptophan-rich diet, which resulted in an accumulation of the AhR ligand indole-3-aledhyde.…”

Indoleamine 2,3‐dioxygenase 1 in coronary atherosclerotic plaque enhances tissue factor expression in activated macrophages

“…The Tampere Vascular Study found that IDO1 expression is elevated in the macrophage‐rich cores of advanced atherosclerotic lesions 25. Levels of Kyn that reflect IDO1 activity are increased in human unstable plaques26 and in rabbit macrophage‐rich atherosclerotic arteries 27. In addition, IDO1 activity in blood significantly and positively correlates with more advanced degrees of atherosclerosis 28.…”

“…This suggests that epacadostat could help to prevent coronary thrombosis. However, further studies are required, because whether or not IDO1 can prevent atherosclerosis remains controversial 26, 43, 44…”