The kynurenine pathway and chronic inflammatory disease
- Project No: NC-14
- Intake: 2024 KIR Non Clinical
PROJECT OVERVIEW
The kynurenine pathway (KP) of tryptophan metabolism drives immune tolerance, suppressing the development of autoimmune disorders such as rheumatoid arthritis (RA). We have shown that inhibition or genetic deletion of indoleamine-2,3-dioxygenase (IDO) exacerbates experimental arthritis and atherosclerosis. In arthritis these changes were associated with increased levels of IL-17 in lymph nodes and joints. Conversely, treatment with the product of IDO, kynurenine, reduced symptoms. Additional studies have confirmed the importance of IDO in promoting the ability of regulatory T cells to maintain immune homeostasis.
IDO expression and activation are induced in myeloid cells during inflammation by a number of factors, including IFN-γ, TLR ligands and ligation of B7 by CTLA-4. The degradation of tryptophan by IDO causes an accumulation of kynurenines that promote the generation and activation of regulatory T cells by triggering aryl hydrocarbon receptor signalling. Regulatory T cells, in turn, upregulate CTLA-4 and induce IDO expression in antigen presenting cells, enabling them to further promote immunoregulation. Recently, a new player has emerged in the form of IL4i1, a secreted L-amino oxidase with a variety of indole substrates. IL4i1 converts tryptophan to indole-3-propionic acid (IPA) which can activate the aryl hydrocarbon receptor directly. IPA is also a direct precursor of the KP metabolite and aryl hydrocarbon receptor ligand, kynurenic acid. The immunosuppressive properties of IL4i1 have been investigated in the field of cancer but its role in autoimmunity and chronic inflammation is largely unexplored.
In this project we will investigate the expression and function of IL4i1 in animal models of immune-driven inflammation, including arthritis and atherosclerosis, and in tissue samples from patients with these conditions. In addition, we will investigate strategies for exploiting the therapeutic potential of IL4i1 using methods well established in our laboratory. We will also investigate the therapeutic potential of inhibition of the KP enzyme, kynurenine-3-monoxygenase (KMO), which promotes accumulation of the aryl hydrocarbon receptor agonists, kynurenine and kynurenic acid. These studies will be accompanied by comprehensive analyses of mechanisms of action.
These studies will expand knowledge on the nature and mechanisms of the relationship between the kynurenine pathway and inflammatory disorders, helping to improve our understanding and, ultimately, treatment of these conditions.
KEYWORDS (5 WORDS)
Indoleamine 2,3 dioxygenase, kynurenine pathway, rheumatoid arthritis, IL4i1, aryl hydrocarbon receptor
TRAINING OPPORTUNITIES
The student will use a variety of in vitro molecular and cellular methods (e.g. RT-PCR, Western blotting, ELISAs), as well as in vivo animal models of chronic inflammatory disease (e.g. collagen-induced arthritis). Receptor silencing or modification using siRNA or CRISPR modifications may be used for more detailed analysis of receptor function. The student will also gain experience in high dimensional flow cytometry and/or mass spectrometry. A core curriculum of lectures will be taken in the first term to provide a solid foundation in a broad range of subjects including musculoskeletal biology, inflammation, epigenetics, translational immunology, data analysis and the microbiome. Students will attend regular seminars within the department and those relevant in the wider University. Students will be expected to present data regularly in lab meetings and departmental seminars, and to attend external conferences to present their research globally. Students will have access to various courses run by the Medical Sciences Division Skills Training Team and other departments. All students are required to attend a 2-day Statistical and Experimental Design course at NDORMS.
KEY PUBLICATIONS (5 maximum)
Stone TW, Williams RO. Modulation of T cells by tryptophan metabolites in the kynurenine pathway. Trends Pharmacol Sci. 2023, 44:442-56.
Huang YS et al. Pharmacological modulation of T cell immunity results in long-term remission of autoimmune arthritis. Proc Natl Acad Sci U S A 2021, 118: e2100939118.
Cole JE et al. Indoleamine 2,3-dioxygenase-1 is protective in atherosclerosis and its metabolites provide new opportunities for drug development. Proc Natl Acad Sci U S A 2015, 112: 13033-8.
Cribbs AP et al. Regulatory T cell function in rheumatoid arthritis is compromised by CTLA-4 promoter methylation resulting in a failure to activate the IDO pathway. Arthritis Rheum 2014, 66: 2344-54.
Criado G et al. Indoleamine 2,3 dioxygenase-mediated tryptophan catabolism regulates accumulation of Th1/Th17 cells in the joint in collagen-induced arthritis. Arthritis Rheum 2009, 60:1342-51.
THEMES (4 key themes)
Immunology, Musculoskeletal Science, Translational Medicine, Medical Technology
CONTACT INFORMATION OF ALL SUPERVISORS
Richard.williams@kennedy.ox.ac.uk