title: 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.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm), Unit 970, Paris Cardiovascular Research Center, and Université Paris-Descartes, Paris, France.
authors.forename: Sarvenaz
authors.initials: S
authors.lastname: Metghalchi
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm), Unit 970, Paris Cardiovascular Research Center, and Université Paris-Descartes, Paris, France.
authors.forename: Padmapriya
authors.initials: P
authors.lastname: Ponnuswamy
authors.affiliation: Assistance Publique, Hôpitaux de Paris (AP-HP), Hôpital St Antoine, UF de Pharmacologie Clinique, URC-EST, and Université Pierre et Marie Curie, Paris, France.
authors.forename: Tabassome
authors.initials: T
authors.lastname: Simon
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm), Unit 970, Paris Cardiovascular Research Center, and Université Paris-Descartes, Paris, France.
authors.forename: Yacine
authors.initials: Y
authors.lastname: Haddad
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm), Unit 970, Paris Cardiovascular Research Center, and Université Paris-Descartes, Paris, France.
authors.forename: Ludivine
authors.initials: L
authors.lastname: Laurans
authors.affiliation: Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK.
authors.forename: Marc
authors.initials: M
authors.lastname: Clément
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm), Unit 970, Paris Cardiovascular Research Center, and Université Paris-Descartes, Paris, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Dalloz
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm), Unit 970, Paris Cardiovascular Research Center, and Université Paris-Descartes, Paris, France.
authors.forename: Mélissa
authors.initials: M
authors.lastname: Romain
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm), Unit 970, Paris Cardiovascular Research Center, and Université Paris-Descartes, Paris, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Esposito
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm), Unit 970, Paris Cardiovascular Research Center, and Université Paris-Descartes, Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Koropoulis
authors.affiliation: Avenir Team Gut Microbiota and Immunity, INSERM U1157/UMR CNRS 7203, UMR 1319 Micalis, INRA, Jouy-en-Josas, France, AP-HP Hôpital St Antoine, Department of Gastroenterology and Université Pierre et Marie Curie 6, Paris, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Lamas
authors.affiliation: Université Paris-Sud, Equipe d'Accueil 4529, UFR de Pharmacie, Chatenay-Malabry, France and AP-HP, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Paul
authors.affiliation: Centre Hospitalo-Universitaire de Dijon, Service de Cardiologie, Dijon, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Cottin
authors.affiliation: Assistance Publique, Hôpitaux de Paris (AP-HP), Hôpital St Antoine, UF de Pharmacologie Clinique, URC-EST, and Université Pierre et Marie Curie, Paris, France.
authors.forename: Salma
authors.initials: S
authors.lastname: Kotti
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm), Unit 970, Paris Cardiovascular Research Center, and Université Paris-Descartes, Paris, France; AP-HP, Hôpital Européen Georges Pompidou, Université Paris-Descartes, Paris, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Bruneval
authors.affiliation: AP-HP, Service de Biochimie and INSERM U942, Hôpital Lariboisière, Paris, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Callebert
authors.affiliation: Laboratory for Experimental Cardiology, University Medical Centre Utrecht, Utrecht, the Netherlands.
authors.forename: Hester
authors.initials: H
authors.lastname: den Ruijter
authors.affiliation: AP-HP, Service de Biochimie and INSERM U942, Hôpital Lariboisière, Paris, France.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Launay
authors.affiliation: AP-HP, Hôpital Européen Georges Pompidou, Université Paris-Descartes, Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Danchin
authors.affiliation: Avenir Team Gut Microbiota and Immunity, INSERM U1157/UMR CNRS 7203, UMR 1319 Micalis, INRA, Jouy-en-Josas, France, AP-HP Hôpital St Antoine, Department of Gastroenterology and Université Pierre et Marie Curie 6, Paris, France.
authors.forename: Harry
authors.initials: H
authors.lastname: Sokol
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm), Unit 970, Paris Cardiovascular Research Center, and Université Paris-Descartes, Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Tedgui
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm), Unit 970, Paris Cardiovascular Research Center, and Université Paris-Descartes, Paris, France. Electronic address: soraya.taleb@inserm.fr.
authors.forename: Soraya
authors.initials: S
authors.lastname: Taleb
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm), Unit 970, Paris Cardiovascular Research Center, and Université Paris-Descartes, Paris, France; Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK. Electronic address: zm255@medschl.cam.ac.uk.
authors.forename: Ziad
authors.initials: Z
authors.lastname: Mallat
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003092:Colitis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005260:Female; D017353:Gene Deletion; D006801:Humans; D007109:Immunity; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000276:immunology*; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology*; D007736:Kynurenic Acid / Q000276:immunology; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000235:genetics / Q000276:immunology / Q000473:pathology
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D016753:Interleukin-10; D007736:Kynurenic Acid