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.

DOI: 10.1016/j.cmet.2015.07.004

5 Figures and Tables

Cite this paper

@article{Metghalchi2015Indoleamine2F, title={Indoleamine 2,3-Dioxygenase Fine-Tunes Immune Homeostasis in Atherosclerosis and Colitis through Repression of Interleukin-10 Production.}, author={Sarvenaz Metghalchi and Padmapriya Ponnuswamy and Tabassome Simon and Yacine Haddad and Ludivine Laurans and Marc Cl{\'e}ment and Marion Dalloz and M{\'e}lissa Romain and Bruno Esposito and Vincent Koropoulis and Bruno Lamas and Jean-Louis Paul and Yves Cottin and Salma Kotti and Patrick Bruneval and Jacques Callebert and Hester den Ruijter and Jean-Marie Launay and Nicolas Danchin and Harry Sokol and Alain Tedgui and Soraya Taleb and Ziad Mallat}, journal={Cell metabolism}, year={2015}, volume={22 3}, pages={460-71} }