Indoleamine 2,3-Dioxygenase Fine-Tunes Immune Homeostasis in Atherosclerosis and Colitis through Repression of Interleukin-10 Production.
Fiche publication
Date publication
septembre 2015
Journal
Cell metabolism
Auteurs
Membres identifiés du Cancéropôle Est :
Pr COTTIN Yves
Tous les auteurs :
Metghalchi S, Ponnuswamy P, Simon T, Haddad Y, Laurans L, Clément M, Dalloz M, Romain M, Esposito B, Koropoulis V, Lamas B, Paul JL, Cottin Y, Kotti S, Bruneval P, Callebert J, den Ruijter H, Launay JM, Danchin N, Sokol H, Tedgui A, Taleb S, Mallat Z
Lien Pubmed
Résumé
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.
Mots clés
Animals, Atherosclerosis, genetics, Colitis, genetics, Female, Gene Deletion, Humans, Immunity, Indoleamine-Pyrrole 2,3,-Dioxygenase, genetics, Interleukin-10, genetics, Kynurenic Acid, immunology, MAP Kinase Signaling System, Male, Mice, Mice, Inbred C57BL, Myocardial Infarction, genetics
Référence
Cell Metab.. 2015 Sep;22(3):460-71