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.

Exploring the Etiological Links behind Neurodegenerative Diseases: Inflammatory Cytokines and Bioactive Kynurenines

“…3-HK and 3-HAA generate ROS and might play a role in the regulation of OS [109]. An elevation of 3-HK levels was related to excitotoxic injury and is observed in patients with NDs [110]. The neurotoxic effect of the intermediates 3-HK and 3-HAA involves the generation of superoxide anion and hydrogen peroxide, which contribute to the oxidative processes implicated in the pathophysiology of meningitis [111].…”

Are Kynurenines Accomplices or Principal Villains in Dementia? Maintenance of Kynurenine Metabolism

“…N-formyl KYN is converted by formamidase to L-KYN, which is a substrate of three downstream metabolites: anthranilic acid (AA) by kynureninase, 3-hydroxy-KYN (3-HK) by KYN-3-monooxygenase (KMO), and KYNA by pyridoxal 5 -phosphate (PLP)-dependent KYN aminotransferases (KATs) [40]. AA and its metabolite, 3-hydroxy-AA (3-HAA), are found to suppress pro-inflammatory cytokine IFN-γ, T and B lymphocyte cell proliferation, and Th1 cell activity and invoke anti-inflammatory cytokine, IL-10 [41]. 3-HK generates highly reactive free radicals.…”

“…KYNA (100 µM) can abolish ROS production produced by FeSO 4 , which is a molecule with a mechanism of toxicity primarily involving O 2− and OH production [117]. Decreased levels of KYNA may provoke an inadequate anti-inflammatory response, resulting in enhanced tissue damage and exceeding cell proliferation during inflammatory in AD, PD, and HD [41]. Increased production of KYNA may be compensatory to limit the inflammatory reaction in AD.…”

Tryptophan Metabolism via Kynurenine Pathway: Role in Solid Organ Transplantation

“…Another aspect, suggesting that TDO participates in the regulation of immune responses after Tx, is its promotion by glucocorticoids, which are included in classical immunosuppressive regimens [32]. Additionally, TDO has been detected in different tumors, such as melanomas, hepatocellular or bladder carcinomas, and its significance in tumor immune escape processes has been investigated [17,96].…”

“…Actually, less than 1% of the available tryptophan is used for protein synthesis, while the remaining 99% serves as a precursor of bioactive metabolites, including serotonin, tryptamine, melatonin and kynurenine, as well as the essential coenzyme nicotinamide adenine dinucleotide (NAD+) [ 13 , 14 ]. The role of tryptophan has been extensively studied in a variety of conditions, such as neuropsychiatric disorders [ 15 ]; autoimmune and allergic diseases [ 16 , 17 ]; infections [ 17 ]; brain tumors [ 18 ] and other cancer types, e.g., breast, bladder, colorectal cancers and melanomas [ 17 , 19 , 20 ]. Tryptophan metabolism via the kynurenine pathway, which is the main route of tryptophan degradation in the human body [ 14 , 21 , 22 ], has gained particular interest in Tx during the last couple of decades.…”