Current Evidence for a Role of the Kynurenine Pathway of Tryptophan Metabolism in Multiple Sclerosis

Abstract

The kynurenine pathway (KP) is the major metabolic pathway of the essential amino acid tryptophan (TRP). Stimulation by inflammatory molecules, such as interferon-γ (IFN-γ), is the trigger for induction of the KP, driving a complex cascade of production of both neuroprotective and neurotoxic metabolites, and in turn, regulation of the immune response and responses of brain cells to the KP metabolites. Consequently, substantial evidence has accumulated over the past couple of decades that dysregulation of the KP and the production of neurotoxic metabolites are associated with many neuroinflammatory and neurodegenerative diseases, including Parkinson’s disease, AIDS-related dementia, motor neurone disease, schizophrenia, Huntington’s disease, and brain cancers. In the past decade, evidence of the link between the KP and multiple sclerosis (MS) has rapidly grown and has implicated the KP in MS pathogenesis. KP enzymes, indoleamine 2,3-dioxygenase (IDO-1) and tryptophan dioxygenase (highest expression in hepatic cells), are the principal enzymes triggering activation of the KP to produce kynurenine from TRP. This is in preference to other routes such as serotonin and melatonin production. In neurological disease, degradation of the blood–brain barrier, even if transient, allows the entry of blood monocytes into the brain parenchyma. Similar to microglia and macrophages, these cells are highly responsive to IFN-γ, which upregulates the expression of enzymes, including IDO-1, producing neurotoxic KP metabolites such as quinolinic acid. These metabolites circulate systemically or are released locally in the brain and can contribute to the excitotoxic death of oligodendrocytes and neurons in neurological disease principally by virtue of their agonist activity at N-methyl-d-aspartic acid receptors. The latest evidence is presented and discussed. The enzymes that control the checkpoints in the KP represent an attractive therapeutic target, and consequently several KP inhibitors are currently in clinical trials for other neurological diseases, and hence may make suitable candidates for MS patients. Underpinning these drug discovery endeavors, in recent years, several advances have been made in how KP metabolites are assayed in various biological fluids, and tremendous advancements have been made in how specimens are imaged to determine disease progression and involvement of various cell types and molecules in MS.

Tryptophan and arginine catabolic enzymes and regulatory cytokines in clinically isolated syndrome and multiple sclerosis

“…Dysfunction in the pathway downstream of IDO in Trp metabolism has been implicated in MS pathogenesis,21 particularly when IDO‐expressing cells leave the circulation and enter the central nervous system. The kynurenines produced by Trp catabolism may be neuroprotective (kynurenic acid, picolinic acid) or neurotoxic (3‐hydroxykynurenine, quinolinic acid), with dysfunction suggested in MS by greater activity in pathways leading to production of neurotoxic mediators 22.…”

Serotonin in Neurological Diseases

“…The kynurenine pathway competes with the melatonin pathway for Trp. Moreover, overactivation of the kynurenine pathway leads to severe imbalance between emerging neuroprotective and neurotoxic metabolites [6,71,72].…”

Altered Microbiota Composition Mediates Depressive Behavior During Chronic Stress

“…During inflammation, IDO1, the enzyme that metabolizes tryptophan to kynurenine, is upregulated by various immune cells 173,[221][222][223] . Kynurenine and kynurenine associated metabolites have a robust anti-inflammatory activity and are protective in the mouse model of MS: experimental autoimmune encephalitis (EAE) 220,224 . Furthermore, mice lacking IDO1 present with a more severe clinical form of the disease 222 .…”

“…Furthermore, mice lacking IDO1 present with a more severe clinical form of the disease 222 . It is also suspected that IFNb, one of the most widely used MS treatments, could be acting by inducing IDO1 expression in immune cells 216,224 .…”

“…While IDO1 expression and the presence of kynurenine metabolites is beneficial on the immune system in the context of MS 220,222,224 , the same player has now been shown to have negative impacts on mental health 84,173,186,193,195,196 . Teasing out the cellular biology of kynurenine metabolism may be particularly impactful for managing depressive behavior in MS/EAE.…”