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.

• Authors: Sarvenaz Metghalchi, Padmapriya Ponnuswamy, Tabassome Simon, Yacine Haddad, Ludivine Laurans, Marc Clément, Marion Dalloz, Mélissa Romain, Bruno Esposito, Vincent Koropoulis, Bruno Lamas, Jean-Louis Paul, Yves Cottin, Salma Kotti, Patrick Bruneval, Jacques Callebert, Hester den Ruijter, Jean-Marie Launay, Nicolas Danchin, Harry Sokol, Alain Tedgui, Soraya Taleb, Ziad Mallat
• Journal: Cell metabolism (Cell Metab) Vol. 22 Issue 3 Pg. 460-71 (Sep 01 2015) ISSN: 1932-7420 [Electronic] United States
• PMID: 26235422 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Indoleamine-Pyrrole 2,3,-Dioxygenase
• Interleukin-10
• Kynurenic Acid

Topics

• Animals
• Atherosclerosis (genetics, immunology, pathology)
• Colitis (genetics, immunology, pathology)
• Female
• Gene Deletion
• Humans
• Immunity
• Indoleamine-Pyrrole 2,3,-Dioxygenase (genetics, immunology)
• Interleukin-10 (genetics, immunology)
• Kynurenic Acid (immunology)
• MAP Kinase Signaling System
• Male
• Mice
• Mice, Inbred C57BL
• Myocardial Infarction (genetics, immunology, pathology)