title: Indoleamine 2,3-dioxygenase-1 is protective in atherosclerosis and its metabolites provide new opportunities for drug development.
abstract: Atherosclerosis is the major cause of cardiovascular disease (CVD), the leading cause of death worldwide. Despite much focus on lipid abnormalities in atherosclerosis, it is clear that the immune system also has important pro- and antiatherogenic functions. The enzyme indoleamine-2,3-dioxygenase (IDO) catalyses degradation of the essential amino acid tryptophan into immunomodulatory metabolites. How IDO deficiency affects immune responses during atherogenesis is unknown and we explored potential mechanisms in models of murine and human atherosclerosis. IDO deficiency in hypercholesterolemic ApoE(-/-) mice caused a significant increase in lesion size and surrogate markers of plaque vulnerability. No significant changes in cholesterol levels were observed but decreases in IL-10 production were found in the peripheral blood, spleen and lymph node B cells of IDO-deficient compared with IDO-competent ApoE(-/-) mice. 3,4,-Dimethoxycinnamoyl anthranilic acid (3,4-DAA), an orally active synthetic derivative of the tryptophan metabolite anthranilic acid, but not l-kynurenine, enhanced production of IL-10 in cultured splenic B cells. Finally, 3,4-DAA treatment reduced lesion formation and inflammation after collar-induced arterial injury in ApoE(-/-) mice, and reduced cytokine and chemokine production in ex vivo human atheroma cell cultures. Our data demonstrate that endogenous production of tryptophan metabolites via IDO is an essential feedback loop that controls atherogenesis and athero-inflammation. We show that the IDO pathway induces production of IL-10 in B cells in vivo and in vitro, suggesting that IDO may induce immunoregulatory functions of B cells in atherosclerosis. The favorable effects of anthranilic acid derivatives in atherosclerosis indicate a novel approach toward therapy of CVD.
authors.affiliation: Nuffield Department of Orthopedics, Rheumatology, and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, University of Oxford, Headington, Oxford OX3 7FY, United Kingdom;
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Cole
authors.affiliation: Nuffield Department of Orthopedics, Rheumatology, and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, University of Oxford, Headington, Oxford OX3 7FY, United Kingdom;
authors.forename: Nagore
authors.initials: N
authors.lastname: Astola
authors.affiliation: Nuffield Department of Orthopedics, Rheumatology, and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, University of Oxford, Headington, Oxford OX3 7FY, United Kingdom;
authors.forename: Adam P
authors.initials: AP
authors.lastname: Cribbs
authors.affiliation: Nuffield Department of Orthopedics, Rheumatology, and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, University of Oxford, Headington, Oxford OX3 7FY, United Kingdom;
authors.forename: Michael E
authors.initials: ME
authors.lastname: Goddard
authors.affiliation: Nuffield Department of Orthopedics, Rheumatology, and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, University of Oxford, Headington, Oxford OX3 7FY, United Kingdom;
authors.forename: Inhye
authors.initials: I
authors.lastname: Park
authors.affiliation: Nuffield Department of Orthopedics, Rheumatology, and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, University of Oxford, Headington, Oxford OX3 7FY, United Kingdom;
authors.forename: Patricia
authors.initials: P
authors.lastname: Green
authors.affiliation: Imperial Vascular Unit, Division of Surgery and Cancer, Imperial College, London W6 8RF, United Kingdom.
authors.forename: Alun H
authors.initials: AH
authors.lastname: Davies
authors.affiliation: Nuffield Department of Orthopedics, Rheumatology, and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, University of Oxford, Headington, Oxford OX3 7FY, United Kingdom;
authors.forename: Richard O
authors.initials: RO
authors.lastname: Williams
authors.affiliation: Nuffield Department of Orthopedics, Rheumatology, and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, University of Oxford, Headington, Oxford OX3 7FY, United Kingdom; marc.feldmann@kennedy.ox.ac.uk claudia.monaco@kennedy.ox.ac.uk.
authors.forename: Marc
authors.initials: M
authors.lastname: Feldmann
authors.affiliation: Nuffield Department of Orthopedics, Rheumatology, and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, University of Oxford, Headington, Oxford OX3 7FY, United Kingdom; marc.feldmann@kennedy.ox.ac.uk claudia.monaco@kennedy.ox.ac.uk.
authors.forename: Claudia
authors.initials: C
authors.lastname: Monaco
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control*; D002934:Cinnamates / Q000737:chemistry / Q000627:therapeutic use; D015195:Drug Design; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000502:physiology*; D007737:Kynurenine / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D062367:ortho-Aminobenzoates / Q000737:chemistry
chemical_list: D001057:Apolipoproteins E; D002934:Cinnamates; C583637:IDO1 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D062367:ortho-Aminobenzoates; C031385:anthranilic acid; D007737:Kynurenine; C065784:3-(3,4-dimethoxyphenyl)propenoic acid
keywords: B cell; atherosclerosis; cardiovascular disease; indoleamine 2,3-dioxygenase; inflammation