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Activation of the Regulatory T-Cell/Indoleamine 2,3-Dioxygenase Axis Reduces Vascular Inflammation and Atherosclerosis in Hyperlipidemic Mice.

ABSTRACT: T-cell activation is characteristic during the development of atherosclerosis. While overall T-cell responses have been implicated in disease acceleration, regulatory T cells (Tregs) exhibit atheroprotective effects. The expression of the enzyme indoleamine 2,3-dioxygenase-1 (IDO1), which catalyzes the degradation of tryptophan (Trp) along the kynurenine pathway, has been implicated in the induction and expansion of Treg populations. Hence, Tregs can reciprocally promote IDO1 expression in dendritic cells (DCs) via reverse signaling mechanisms during antigen presentation. In this study, we hypothesize that triggering the "Treg/IDO axis" in the artery wall is atheroprotective. We show that apolipoprotein B100-pulsed tumor growth factor beta 2-treated tolerogenic DCs promote de novo FoxP3+ Treg expansion in vivo. This local increase in Treg numbers is associated with increased vascular IDO1 expression and a robust reduction in the atherosclerotic burden. Using human primary cell cultures, we show for the first time that IDO1 expression and activity can be regulated by cytotoxic T-lymphocyte associated protein-4, which is a constitutive molecule expressed and secreted by Tregs, in smooth muscle cells, endothelial cells, and macrophages. Altogether, our data suggest that Tregs and IDO1-mediated Trp metabolism can mutually regulate one another in the vessel wall to promote vascular tolerance mechanisms that limit inflammation and atherosclerosis.

SUBMITTER: Forteza MJ

PROVIDER: S-EPMC5949314 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Activation of the Regulatory T-Cell/Indoleamine 2,3-Dioxygenase Axis Reduces Vascular Inflammation and Atherosclerosis in Hyperlipidemic Mice.

Forteza Maria J MJ Polyzos Konstantinos A KA Baumgartner Roland R Suur Bianca E BE Mussbacher Marion M Johansson Daniel K DK Hermansson Andreas A Hansson Göran K GK Ketelhuth Daniel F J DFJ

Frontiers in immunology 20180507

T-cell activation is characteristic during the development of atherosclerosis. While overall T-cell responses have been implicated in disease acceleration, regulatory T cells (Tregs) exhibit atheroprotective effects. The expression of the enzyme indoleamine 2,3-dioxygenase-1 (IDO1), which catalyzes the degradation of tryptophan (Trp) along the kynurenine pathway, has been implicated in the induction and expansion of Treg populations. Hence, Tregs can reciprocally promote IDO1 expression in dendr ...[more]

PMID: 29867939

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Project description:Successful long-term treatment of type-1 diabetes mainly relies on replacement of β-cells via islet transplantation. Donor shortage is one of the main obstacles preventing transplantation from becoming the treatment of choice. Although animal organs could be an alternative source for transplantation, common immunosuppressive treatments demonstrate low efficacy in preventing xenorejection. Immunoprotective effects of indoleamine 2,3-dioxygenase (IDO) on T-cell mediated allorejection has been extensively studied. Our studies revealed that IDO expression by fibroblasts, induced apoptosis in T-cells while not affecting non-immune cell survival/function. Since macrophages play a pivotal role in xenograft rejection, herein we investigated the effect of IDO-induced tryptophan deficiency/kynurenine accumulation on macrophage function/survival. Moreover, we evaluated the local immunosuppressive effect of IDO on islet-xenograft protection. Our results indicated that IDO expression by bystander fibroblasts significantly reduced the viability of primary macrophages via apoptosis induction. Treatment of peritoneal macrophages by IDO-expressing fibroblast conditioned medium significantly reduced their proinflammatory activity through inhibition of iNOS expression. To determine whether IDO-induced tryptophan starvation or kynurenine accumulation is responsible for macrophage apoptosis and inhibition of their proinflammatory activity, Raw264.7 cell viability and proinflammatory responses were evaluated in tryptophan deficient medium or in the presence of kynurenine. Tryptophan deficiency, but not kynurenine accumulation, reduced Raw264.7 cell viability and suppressed their proinflammatory activity. Next a three-dimensional islet-xenograft was engineered by embedding rat islets within either control or IDO-expressing fibroblast-populated collagen matrix. Islets morphology and immune cell infiltration were then studied in the xenografts transplanted into the C57BL/6 mouse renal sub-capsular space. Local IDO significantly decreased the number of infiltrating macrophages (11 ± 1.47 vs. 70.5 ± 7.57 cells/HPF), T-cells (8.75 ± 1.03 vs. 75.75 ± 5.72 cells/HPF) and iNOS expression in IDO-expressing xenografts versus controls. Islet morphology remained intact in IDO-expressing grafts and islets were strongly stained for insulin/glucagon compared to control. These findings support the immunosuppressive role of IDO on macrophage-mediated xeno-rejection.

Dataset Information

Activation of the Regulatory T-Cell/Indoleamine 2,3-Dioxygenase Axis Reduces Vascular Inflammation and Atherosclerosis in Hyperlipidemic Mice.

Publications

Activation of the Regulatory T-Cell/Indoleamine 2,3-Dioxygenase Axis Reduces Vascular Inflammation and Atherosclerosis in Hyperlipidemic Mice.

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