Abstract 675: Role of Indoleamine 2,3-dioxygenase in Atherosclerosis Development
Indoleamine 2,3-dioxygenase (Ido), a rate-limiting enzyme that catalizes the degradation of tryptophan along the kynurenine pathway, is seen as a major mediator of immune tolerance. Our purpose is to study the role of Ido in an inflammatory disease which is atherosclerosis. We showed that surprisingly the total Ido deletion in Ldlr-/- mice (Ldlr-/-Ido-/-) or in mice reconstituted with Ido-/- bone marrow showed a significant reduction in atherosclerosis (p<0.05). Then, we examined the inflammatory profile of cells known to express Ido such as macrophages. Interestingly, Ido-/- macrophages showed a significant increase of IL-10 expression compared with controls (p<0.05).To examine the role of IL-10 in Ido-mediated effect, we made double knockout- mice Ido-/-Il-10-/-. Importantly, the resistance of Ido-deficient mice to enhanced atherosclerosis and immune activation is broken in Ido-/-Il-10-/- mice, which then show exaggerated immune responses and develop a very severe colitis. We also showed that kynurenic acid, a kynurenine-derived metabolite, is responsible for reduced Il-10 production through inhibition of Erk1/2 phosphorylation and increased of atherosclerosis development (p<0.05). Our results reveal a previously unsuspected Janus-faced Ido that actively represses Il-10 while promoting other pathways of immune tolerance, thereby introducing a higher degree of complexity in immune regulation.
Author Disclosures: S. Taleb: None. P. Ponnuswamy: None. T. Alain: None. Z. Mallat: None.
- © 2014 by American Heart Association, Inc.