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Role of the Kynurenine Pathway in Immune-Mediated Inflammation

  • Adam P. Cribbs
  • Richard O. Williams

Abstract

Indoleamine 2,3-dioxygenase (IDO) plays a key role in immune homeostasis via depletion of tryptophan and accumulation of kynurenines and is recognized as an important factor contributing to suppression of antitumor immune responses. However, the possibility of harnessing the IDO pathway for the therapy of autoimmune disease represents an intriguing possibility, and in this review, we highlight recent research on the involvement of IDO in immune-mediated inflammatory diseases, with a focus on rheumatoid arthritis. Inhibition of IDO was shown to exacerbate experimental arthritis and increase numbers of pathogenic Th1 and Th17 cells in the joints and draining lymph nodes. Analysis of the kinetics of expression of kynurenine pathway enzymes in animal models also pointed to a potential role for tryptophan metabolites in disease resolution and administration of l-kynurenine or [3,4-dimethoxycinnamonyl]-anthranilic acid (a synthetic derivative of 3-hydroxyanthranilic acid) reduced the severity of disease. A more recent study has identified an association between defective regulatory T cells in rheumatoid arthritis with reduced capacity to activate the kynurenine pathway. These findings suggest that strategies to activate IDO in a targeted manner may be effective in the therapy of autoimmune disease.

Keywords

Rheumatoid arthritis Collagen-induced arthritis Indoleamine 2,3-dioxygenase Inflammation Autoimmunity 

List of Abbreviations

1-MT

1-methyl tryptophan

APCs

Antigen-presenting cells

AHR

Aryl hydrocarbon receptor

CIA

Collagen-induced arthritis

CTLA-4

Cytotoxic T-lymphocyte-associated protein 4

DC

Dendritic cell

DMARDs

Disease-modifying anti-rheumatic drugs

EAE

Experimental autoimmune encephalomyelitis

GPR35

G-protein-coupled receptor 35

GWAS

Genome-wide association studies

IDO

Indoleamine 2,3-dioxygenase

IFN

Interferon

IL-1

Interleukin 1

IRF1

Interferon-regulatory factor

LPS

Lipopolysaccharide

MHC

Major histocompatibility complex

NK

Natural killer

NOD

Nonobese diabetic

NFAT

Nuclear factor of activated T cells

pDCs

Plasmacytoid DCs

Tregs

Regulatory T cells

RA

Rheumatoid arthritis

STAT1

Signal transducer and activator of transcription 1

TCR

T cell receptor

Th

T helper

TGF

Transforming growth factor

TDO

Tryptophan 2,3-dioxygenase

TTS

Tryptophanyl-tRNA-synthetase

TNF

Tumor necrosis factor

T1D

Type 1 diabetes

Notes

Funding

This work was supported by the Kennedy Trust for Rheumatology Research.

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Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Kennedy Institute of RheumatologyUniversity of OxfordOxfordUK
  2. 2.Botnar Research Centre, Institute of musculoskeletal SciencesOxfordUK

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