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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.

SUBMITTER: Boros FA

PROVIDER: S-EPMC6851023 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Immunomodulatory Effects of Genetic Alterations Affecting the Kynurenine Pathway.

Boros Fanni A FA Vécsei László L

Frontiers in immunology 20191106

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 ...[more]

PMID: 31781097

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Project description:Reports of neurodegenerative and psychiatric disease in former athletes have increased public concern about the acute and chronic effects of sport-related concussions (SRC). The biological factors underlying individual differences in the psychiatric sequalae of SRC and their role in potential long-term negative outcomes have not been determined. One understudied biological consequence of the known inflammatory response to concussion is the activation of a key immunoregulatory pathway, the kynurenine pathway (KP). Activation of the KP produces several neuroactive metabolites that have been associated with psychiatric and neurodegenerative diseases. We tested the hypothesis that SRC results in an elevation of serum KP metabolites with neurotoxic properties (quinolinic acid [QuinA], 3-hydroxykynurenine [3HK]) together with a reduction in the neuroprotective metabolite kynurenic acid (KynA), and that these metabolites would predict post-concussion psychological symptoms. Additionally, because brain injury is thought to prime the immune system, a secondary goal was to test the hypothesis that athletes with acute SRC and a history of prior SRC would have elevated neurotoxic relative to neuroprotective KP metabolites compared to athletes that were concussed for the first time. High school and collegiate football players (N = 1136) were enrolled at a preseason baseline visit that included clinical testing and blood specimen collection. Athletes that suffered a SRC (N = 59) completed follow-up visits within 6-hours (early-acute), at 24-48 h (late-acute) and at 8, 15, and 45 days post-injury. Uninjured contact sport (CC; N = 54) and non-contact sport athletes completed similar visits and served as controls (NCC; N = 30). SRC athletes had significantly elevated psychological symptoms, assessed using the Brief Symptom Inventory-18 (BSI), acutely following injury relative to both control groups. There was a group-by-visit interaction on the ratio of KynA to 3HK in serum, a neuroprotective index, with elevated KynA/3HK in athletes with SRC at the early-acute visit relative to later visits. Importantly, athletes with greater elevation in this neuroprotective index at the early-acute visit reported fewer depressive symptoms at the late-acute visit. Finally, SRC athletes with prior concussion had significantly lower serum KynA/QuinA at all visits compared to SRC athletes with no prior concussion, an effect driven by elevated QuinA in SRC athletes with prior concussion. These results suggest that early-acute activation of the KynA branch of the KP may protect against the development of depressive symptoms following concussion. Furthermore, they highlight the potential of serum QuinA as a biomarker for repetitive head injury and provide insight into possible mechanisms linking prior concussion with subsequent injury.

Dataset Information

Immunomodulatory Effects of Genetic Alterations Affecting the Kynurenine Pathway.

Publications

Immunomodulatory Effects of Genetic Alterations Affecting the Kynurenine Pathway.

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