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Role of the Kynurenine Pathway in Immune-Mediated Inflammation

  • Chapter
Targeting the Broadly Pathogenic Kynurenine Pathway

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.

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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

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Funding

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

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Authors and Affiliations

  1. Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford, OX3 7FY, UK

    Adam P. Cribbs & Richard O. Williams

  2. Botnar Research Centre, Institute of musculoskeletal Sciences, Windmill Road, Oxford, OX3 7LD, UK

    Adam P. Cribbs

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  1. Adam P. Cribbs
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Correspondence to Adam P. Cribbs .

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Editors and Affiliations

  1. Chairman, Department of Neurosurgery, Wayne State University, Detroit, Michigan, USA

    Sandeep Mittal

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Cribbs, A.P., Williams, R.O. (2015). Role of the Kynurenine Pathway in Immune-Mediated Inflammation. In: Mittal, S. (eds) Targeting the Broadly Pathogenic Kynurenine Pathway. Springer, Cham. https://doi.org/10.1007/978-3-319-11870-3_7

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