Immunomodulatory Effects of Genetic Alterations Affecting the Kynurenine Pathway

Abstract

Several enzymes and metabolites of the kynurenine pathway (KP) have immunomodulatory effects. Modulation of the activities and levels of these molecules might be of particular importance under disease conditions when the amelioration of overreacting immune responses is desired. Results obtained by the use of animal and tissue culture models indicate that by eliminating or decreasing activities of key enzymes of the KP, a beneficial shift in disease outcome can be attained. This review summarizes experimental data of models in which IDO, TDO, or KMO activity modulation was achieved by interventions affecting enzyme production at a genomic level. Elimination of IDO activity was found to improve the outcome of sepsis, certain viral infections, chronic inflammation linked to diabetes, obesity, aorta aneurysm formation, and in anti-tumoral processes. Similarly, lack of TDO activity was advantageous in the case of anti-tumoral immunity, while KMO inhibition was found to be beneficial against microorganisms and in the combat against tumors, as well. On the other hand, the complex interplay among KP metabolites and immune function in some cases requires an increase in a particular enzyme activity for the desired immune response modulation, as was shown by the exacerbation of liver fibrosis due to the elimination of IDO activity and the detrimental effects of TDO inhibition in a mouse model of autoimmune gastritis. The relevance of these studies concerning possible human applications are discussed and highlighted. Finally, a brief overview is presented on naturally occurring genetic variants affecting immune functions via modulation of KP enzyme activity.

Keywords: IDO; KMO; TDO; genetic manipulation; immunomodulation; kynurenine pathway.

Figure 1

The kynurenine pathway of tryptophan metabolism. Enzymes of the KP metabolise Trp into products possessing immune- and neuromodulatory properties. By the utilization of Trp and generation of NAD coenzyme precursor the KP has profound effects on cellular protein and energy metabolism. Several internal metabolites of the pathway play role on redox regulation and have neuroprotective - or neurotoxic effects. Immune functions are modified by the KP both directly, via immuno modulatory metabolites and indirectly, via changing the metabolism of immune cells by altering amino acid availability, redox status and energy balance. Abbreviations: Trp: tryptophan; TDO:tryptophan 2,3-dioxygenase; IDO:indoleamine 2,3-dioxygenase; N-formyl KYN:N-formyl-kynurenine; L-KYN:L-kynurenine; KAT:kynurenine aminotransferase; KYNA: kynurenic acid; KYNU:kynureninase; AA:anthranilic acid; KMO:kynurenine 3-monooxygenase; 3-HK:3-hydroxy kynurenine; XA: xanthurenic acid; KYNU:kynureninase; 3-HAA: 3-hydroxyanthranilic acid; 3-HAO:3-hydroxyanthranilate 3,4-dioxygenase; ACMS: 2-amino-3-carboxymuconate-semialdehyde; ACMSD: aminocarboxymuconate-semialdehyde-decarboxylase; PIC: picolinic acid; QUIN: quinolinic acid; QPRTase:quinolinate phosphoribosyltransferase; NAD⁺: nicotinamide adenine dinucleotide; CNS: central nervous system.

Figure 2

Overview of pathways leading to IDO enzyme production and regulation. IDO activity is regulated at different levels. Its substrate Trp and cofactor heme are positive regulators of the enzyme, whereas antioxidants and NO act as inhibitors. Phosphorylation at tyrosine side chains and ubiquitination modulate IDO activity and half life. At the level of transcription several cis regulatory elements of the IDO promoter collect regulatory signals via binding of transcription factors and epigenetic regulators, which respond to signals arriving from receptors that are activated by cytokines and other immunomodulatory molecules. Extracellular signals produced by other cells or pathogens and intracellular signals, such as cytosolic dsDNA can both induce IDO expression and feed-back regulation of the production has also been described [see text for details and (60)]. Abbreviations: IFN: interferon; TNF: tumor necrosis factor; TGFβ: transforming growth factor beta; LPS: lipopolysaccharide; dsDNA: double strand DNA; TLR: toll-like receptor; TGFBR: transforming growth factor beta receptor; IFNBR: interferon beta receptor; IFNGR: interferon gamma receptor; TNFR: tumor necrosis factor receptor; AHR: aryl hydrocarbon receptor; ISRE: IFN stimulated response element; DRE: dendritic cell response element; GAS: gamma-activated sequences; HDAC: histone deacetylase; ~P: phosphorylation; IDO: indoleamine 2,3-dioxygenase; SOCS3: suppressor of cytokine signaling 3; Trp: tryptophan; NO: nitrogen oxide.

Figure 3

Effects on IDO activity on immune responses. IDO is expressed by various cells of the immune system in response to activation by inflammatory markers such as IFNs, ILs, TNFs, PGs and LPS. By decreasing the amount of available Trp IDO activates the GCN2 stress-kinase pathway leading to T cell anergy and cell cycle arrest, inhibits the mTOR pathway thus diminishing T cell proliferation. By increasing KP metabolite concentrations IDO also contributes to the apoptosis of effector T cells and promotes the formation of T cells of the regulatory subtype. Via these mechanisms IDO might exert profound effects on both systemic and local immune responses. Abbreviations: IFNs: interferons; Ils: interleukins; TNFs: tumor necrosis factors; PGs: prostaglandines; LPS: lipopolysaccharide; DC: dendritic cell; IDO: indoleamine 2,3-dioxygenase; Trp: tryptophan; KP: kynurenine pathway; mTOR: mammalian target of rapamycin.