Kynurenine Metabolism in Immune Regulation and Neurological Disorders

The kynurenine pathway is the principal route for the non-protein metabolism of the essential amino acid tryptophan, catalysed initially by indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO). Through sequential enzymatic steps, this pathway generates metabolites with potent immunomodulatory and neuroactive properties. Depletion of tryptophan in local microenvironments starves proliferating T cells, while the accumulation of kynurenine and downstream products such as kynurenic acid and quinolinate shapes immune tolerance via activation of receptors including the aryl hydrocarbon receptor and G protein-coupled receptors. In the central nervous system, these metabolites exert dual roles: quinolinate acts as an excitotoxin through NMDA receptor overactivation, contributing to neurodegeneration and neuroinflammation, whereas kynurenic acid confers neuroprotection by antagonising excitatory neurotransmission. Dysregulation of this pathway has been implicated in cancer immune evasion, autoimmunity, psychiatric disorders and neurodegenerative diseases such as Alzheimer’s and Huntington’s. Bridging immunology and neuroscience, research across diverse models has begun to translate mechanistic insights into therapeutic strategies—ranging from enzyme inhibitors and receptor antagonists to locally anchored immunomodulatory enzymes—to rebalance immune homeostasis and protect neural integrity.

Research from Nature Portfolio

Recent studies have demonstrated that anchoring IDO to inflamed tissue via a fusion with galectin-3 achieves sustained local immunosuppression without systemic side effects, restoring tissue homoeostasis in rodent models of psoriasis, osteoarthritis and periodontal disease. In oncology, tumour-derived kynurenine has been shown to hijack haematopoietic progenitors by activating the aryl hydrocarbon receptor–RUNX1 axis, driving skewed differentiation towards megakaryocytes and contributing to cancer-associated thrombocytosis. In glioblastoma, aberrant accumulation of quinolinate within the tumour microenvironment engages NMDA receptors on macrophages, triggering FOxO1/PPARγ signalling and fostering a profoundly immune-tolerant niche; genetic inhibition of quinolinate synthesis re-sensitises tumours to immune attack, highlighting novel targets for brain-tumour immunotherapy.

Kynurenine Metabolism in Immune Regulation and Neurological Disorders publication trend

The graph below shows the total number of articles in kynurenine metabolism in immune regulation and neurological disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Kynurenine: A central metabolite of tryptophan catabolism that regulates immune cell differentiation and serves as precursor for neuroactive compounds.

Indoleamine 2,3-dioxygenase (IDO): The rate-limiting enzyme that converts tryptophan into N-formylkynurenine, initiating the kynurenine pathway and mediating local immune tolerance.

Aryl hydrocarbon receptor (AhR): A ligand-activated transcription factor that senses kynurenine pathway metabolites to modulate gene expression in immune and neural cells.

Quinolinate: A downstream catabolite that acts as an NMDA receptor agonist, linked to excitotoxicity and immune suppression in brain tumours.

Kynurenic acid: A neuroprotective product of the kynurenine pathway that antagonises excitatory receptors and signals through GPR35 and AhR to influence inflammation.

References

1. Suppression of local inflammation via galectin-anchored indoleamine 2,3-dioxygenase. Nature Biomedical Engineering (2023).
2. Tumor cell-released kynurenine biases MEP differentiation into megakaryocytes in individuals with cancer by activating AhR–RUNX1. Nature Immunology (2023).
3. Quinolinate promotes macrophage-induced immune tolerance in glioblastoma through the NMDAR/PPARγ signaling axis. Nature Communications (2023).
4. Immune regulation through tryptophan metabolism. Experimental & Molecular Medicine (2023).
5. Kynurenic Acid: The Janus-Faced Role of an Immunomodulatory Tryptophan Metabolite and Its Link to Pathological Conditions. Frontiers in Immunology (2018).