[^1]
[^2]
[^3]
[^4]
| Symbol | IDO1 |
| Full Name |
Indoleamine 2,3-Dioxygenase 1 |
| Chromosome |
8p11.21 |
| NCBI Gene |
3620 |
| Ensembl |
ENSG00000131203 |
| OMIM |
147435 |
| UniProt |
P14902 |
| Diseases |
[Alzheimer's Disease](/diseases/alzheimers), [Parkinson's Disease](/diseases/parkinsons-disease), [ALS](/diseases/als), [Huntington's Disease](/diseases/huntingtons), Major Depression |
| Expression |
Microglia, [astrocytes](/entities/astrocytes), macrophages, dendritic cells |
Rate-limiting kynurenine pathway enzyme
IFN-γ–inducible
Produces neurotoxic quinolinic acid
Immune checkpoint |
IDO1 (Indoleamine 2,3-Dioxygenase 1) is a gene on chromosome 8p11.21 encoding the rate-limiting enzyme of the kynurenine pathway — the major route of tryptophan catabolism outside the liver. IDO1 catalyzes the oxidative cleavage of the indole ring of L-tryptophan to produce N-formylkynurenine, initiating a metabolic cascade that generates both neuroprotective metabolites (kynurenic acid) and neurotoxic metabolites (quinolinic acid, 3-hydroxykynurenine). In the brain, IDO1 is strongly induced in microglia and astrocytes by IFN-γ and other inflammatory signals, making it a critical link between neuroinflammation and neurodegeneration across Alzheimer's, Parkinson's, Huntington's, and ALS.
Key takeaway: IDO1 is the rate-limiting enzyme that diverts tryptophan into the kynurenine pathway during neuroinflammation. The resulting shift from serotonin production to neurotoxic quinolinic acid production drives excitotoxicity, oxidative stress, and neuronal death across multiple neurodegenerative diseases.
¶ Gene Structure and Expression
IDO1 spans approximately 15 kb on chromosome 8p11.21, comprising 10 exons encoding a 403-amino acid heme-containing oxidoreductase. IDO1 is located adjacent to IDO2 (which has similar but weaker enzymatic activity). The gene promoter contains multiple interferon-stimulated response elements (ISREs) and GAS elements, reflecting its strong inducibility by interferons.
IDO1 expression in the CNS is minimal under basal conditions but dramatically upregulated during inflammation:
- Microglia: Primary source of brain IDO1; produces the neurotoxic branch metabolites (quinolinic acid, 3-OH-kynurenine)
- Astrocytes: Express IDO1 and preferentially produce the neuroprotective metabolite kynurenic acid (via KAT enzymes)
- Perivascular macrophages: High IDO1 induction at blood-brain barrier
- Neurons: Low/absent IDO1 expression; neurons are consumers, not producers, of kynurenine metabolites
Expression data is available from the Allen Human Brain Atlas.
IDO1 is one of the most strongly interferon-inducible genes:
- IFN-γ (primary inducer): Activates IDO1 transcription via JAK/STAT1 pathway → GAS elements in promoter
- IFN-α/β: Type I interferons also induce IDO1 via ISRE elements
- TNF-α: Synergizes with IFN-γ for maximal IDO1 induction
- NF-κB: Inflammatory signaling upregulates IDO1
- TLR4: LPS and DAMPs (including HMGB1) induce IDO1 through TLR signaling
- Aryl hydrocarbon receptor (AhR): Kynurenine itself activates AhR, which further upregulates IDO1 (positive feedback loop)
IDO1 catalyzes the first and rate-limiting step of the kynurenine pathway:
L-Tryptophan + O₂ → N-Formylkynurenine
The enzyme:
- Uses molecular oxygen and a heme cofactor
- Has a catalytic mechanism involving superoxide radical intermediates
- Shows Michaelis-Menten kinetics with Km ~20 μM for L-tryptophan
- Is inhibited by 1-methyltryptophan (1-MT), the classic IDO inhibitor
IDO1 activation diverts tryptophan through the kynurenine pathway, generating metabolites with profoundly different neurological effects:
Neuroprotective branch (astrocytes):
- L-Kynurenine → Kynurenic acid (KYNA) (via KAT enzymes)
- KYNA is an NMDA receptor antagonist and α7-nicotinic receptor antagonist
- KYNA is neuroprotective by reducing excitotoxicity
Neurotoxic branch (microglia):
- L-Kynurenine → 3-Hydroxykynurenine (3-HK) → 3-Hydroxyanthranilic acid → Quinolinic acid (QUIN)
- 3-HK generates reactive oxygen species, causing oxidative stress
- QUIN is an NMDA receptor agonist that causes excitotoxicity
- QUIN generates free radicals through Fenton chemistry
- QUIN promotes tau hyperphosphorylation
IDO1 also functions as an immune checkpoint:
- Depletes tryptophan in the local microenvironment, inhibiting T cell proliferation
- Generates kynurenine, which activates AhR on regulatory T cells (Tregs)
- Creates an immunosuppressive milieu around inflammatory foci
- This immune checkpoint function is exploited by tumors (hence IDO1 inhibitors in oncology)
IDO1 is centrally involved in AD through multiple mechanisms:
- Upregulation: IDO1 expression and activity are markedly increased in AD hippocampus, temporal cortex, and frontal cortex compared to age-matched controls
- Amyloid-β induction: Aβ oligomers directly induce IDO1 expression in microglia via TLR4 and IFN-γ signaling
- Quinolinic acid accumulation: QUIN levels are elevated in AD brain regions, colocalizing with neurofibrillary tangles
- Tau phosphorylation: QUIN activates NMDA receptors, leading to calcium influx and activation of GSK3β and CDK5, promoting tau hyperphosphorylation
- Serotonin depletion: Tryptophan diversion reduces serotonin synthesis, contributing to depression and behavioral symptoms in AD
- KYN/TRP ratio biomarker: Elevated kynurenine-to-tryptophan ratio in CSF and plasma is a biomarker of neuroinflammation-driven tryptophan catabolism in AD
In PD:
- IDO1 is upregulated in substantia nigra microglia
- Quinolinic acid contributes to dopaminergic neuron excitotoxicity
- 3-HK generates ROS that exacerbate mitochondrial dysfunction in dopaminergic neurons
- α-Synuclein aggregates activate microglia and induce IDO1
- IDO1 inhibition is neuroprotective in MPTP and 6-OHDA PD models
The kynurenine pathway is profoundly dysregulated in HD:
- Quinolinic acid levels are elevated in HD striatum, directly linking excitotoxicity to disease
- Intrastriatal injection of QUIN reproduces HD-like striatal neurodegeneration in animal models
- 3-HK levels increase progressively with HD severity
- The QUIN/KYNA ratio is shifted toward neurotoxicity in HD brain
- IDO1 inhibition reduces striatal QUIN and improves phenotype in HD mice
In amyotrophic lateral sclerosis:
- Kynurenine pathway activation in spinal cord microglia
- Elevated QUIN in ALS motor cortex and spinal cord
- Tryptophan metabolism alterations detectable in ALS patient plasma
- IDO1 inhibition reduces motor neuron loss in SOD1 mouse models
¶ Depression and Neuropsychiatric Symptoms
IDO1 activation directly links inflammation to depression:
- Tryptophan depletion reduces serotonin (5-HT) synthesis
- IFN-α therapy (for hepatitis C) induces IDO1 and causes depression in ~30% of patients
- Depression in AD and PD patients correlates with IDO1 activation markers
- This is the molecular basis of "sickness behavior" during infection
| Stimulus |
Cell Type |
IDO1 Fold-Induction |
Peak Time |
| IFN-γ |
Microglia |
50-200× |
24-48 h |
| IFN-γ + TNF-α |
Microglia |
200-500× |
24 h |
| LPS |
Microglia |
10-50× |
12-24 h |
| Aβ oligomers |
Microglia |
5-20× |
48 h |
| α-Synuclein |
Microglia |
5-15× |
48 h |
| IFN-γ |
Astrocytes |
20-100× |
24-48 h |
In AD brains, IDO1 immunoreactivity is highest in:
- Hippocampus (especially CA1, dentate gyrus)
- Entorhinal cortex
- Temporal neocortex
- Frontal cortex
- Minimal in cerebellum (disease-resistant region)
- 1-Methyltryptophan (1-MT): Classic competitive IDO1 inhibitor; both L- and D-isomers have been studied. Neuroprotective in multiple preclinical models.
- Epacadostat (INCB024360): Selective, potent IDO1 inhibitor developed for oncology; being repurposed for neurodegeneration studies
- Navoximod (GDC-0919): Another clinical-stage IDO1 inhibitor
- BMS-986205 (linrodostat): Irreversible IDO1 inhibitor in clinical trials for cancer
- Natural inhibitors: Berberine, curcumin, and certain flavonoids have IDO1 inhibitory activity
- KMO inhibitors: Block conversion of kynurenine to 3-HK, reducing both 3-HK and QUIN; Ro 61-8048, GSK180 are lead compounds
- Kynurenic acid analogs: Synthetic KYNA derivatives that cross the BBB (KYNA itself has poor BBB penetration)
- QPRT enhancers: Increase quinolinic acid phosphoribosyltransferase activity to clear QUIN
- IDO1 is a validated drug target in oncology with multiple clinical-stage inhibitors
- Repurposing these inhibitors for neurodegenerative diseases is an active area of research
- Biomarker-guided treatment (KYN/TRP ratio) could identify patients most likely to benefit
- Combination with anti-inflammatory therapies may provide synergistic neuroprotection