Role of indoleamine 2,3-dioxygenase in health and disease

Abstract

IDO1 (indoleamine 2,3-dioxygenase 1) is a member of a unique class of mammalian haem dioxygenases that catalyse the oxidative catabolism of the least-abundant essential amino acid, L-Trp (L-tryptophan), along the kynurenine pathway. Significant increases in knowledge have been recently gained with respect to understanding the fundamental biochemistry of IDO1 including its catalytic reaction mechanism, the scope of enzyme reactions it catalyses, the biochemical mechanisms controlling IDO1 expression and enzyme activity, and the discovery of enzyme inhibitors. Major advances in understanding the roles of IDO1 in physiology and disease have also been realised. IDO1 is recognised as a prominent immune regulatory enzyme capable of modulating immune cell activation status and phenotype via several molecular mechanisms including enzyme-dependent deprivation of L-Trp and its conversion into the aryl hydrocarbon receptor ligand kynurenine and other bioactive kynurenine pathway metabolites, or non-enzymatic cell signalling actions involving tyrosine phosphorylation of IDO1. Through these different modes of biochemical signalling, IDO1 regulates certain physiological functions (e.g. pregnancy) and modulates the pathogenesis and severity of diverse conditions including chronic inflammation, infectious disease, allergic and autoimmune disorders, transplantation, neuropathology and cancer. In the present review, we detail the current understanding of IDO1's catalytic actions and the biochemical mechanisms regulating IDO1 expression and activity. We also discuss the biological functions of IDO1 with a focus on the enzyme's immune-modulatory function, its medical implications in diverse pathological settings and its utility as a therapeutic target.

Mouse chronic social stress increases blood and brain kynurenine pathway activity and fear behaviour: Both effects are reversed by inhibition of indoleamine 2,3-dioxygenase

“…These include proinflammatory cytokines, and factors governing the synthesis of the haem prosthetic group that is essential for the formation of the active IDO1 holoenzyme (Yeung et al, 2015). These post-translational factors constitute novel targets for regulating stress-induced increased IDO1-KYN pathway activity.…”

Activation of the tryptophan/serotonin pathway is associated with severity and predicts outcomes in pneumonia: results of a long-term cohort study

“…Its antimicrobial effect was thought to exist through a breakdown of TRP as TRP is essential for the growth of microorganisms. However, recent studies have demonstrated its novel role as a strong inhibitor of T cell proliferation [2]. Sepsis-induced elevation of 5-HT has recently been discovered in a mouse model where high levels of 5-HT facilitated endothelial hyperpermeability [3].…”

“…Particularly TRP and its metabolites are thought to be altered during infections as part of the immune reaction [2,3]. There are two metabolic pathways in the breakdown of TRP [4] (illustrated in Figure 1).…”

Binding properties of different categories of IDO1 inhibitors: a microscale thermophoresis study

“…Many downstream products of KP have been identified as biologically active compounds (3)(4)(5), showing the capability to regulate inflammatory responses through several mechanisms [4]. An increasing body of evidence has thus thrust IDO1 under the spotlight as a key druggable target to control the balance between immune-tolerance and immune-inflammatory responses [5,6]. Noteworthy, signaling functions of IDO1 have also been discovered [7,8].…”

“…The 95% of dietary L-Trp (1, Figure 1) is catabolized through the kynurenine pathway (KP), with IDO1 being a heme-containing enzyme that catalyzes the first and rate-limiting step of the pathway to produce N-formyl-kynurenine (2) [3]. Many downstream products of KP have been identified as biologically active compounds (3)(4)(5), showing the capability to regulate inflammatory responses through several mechanisms [4]. An increasing body of evidence has thus thrust IDO1 under the spotlight as a key druggable target to control the balance between immune-tolerance and immune-inflammatory responses [5,6].…”