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      Tryptophan Metabolism in Inflammaging: From Biomarker to Therapeutic Target

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          Abstract

          Inflammation aims to restore tissue homeostasis after injury or infection. Age-related decline of tissue homeostasis causes a physiological low-grade chronic inflammatory phenotype known as inflammaging that is involved in many age-related diseases. Activation of tryptophan (Trp) metabolism along the kynurenine (Kyn) pathway prevents hyperinflammation and induces long-term immune tolerance. Systemic Trp and Kyn levels change upon aging and in age-related diseases. Moreover, modulation of Trp metabolism can either aggravate or prevent inflammaging-related diseases. In this review, we discuss how age-related Kyn/Trp activation is necessary to control inflammaging and alters the functioning of other metabolic faiths of Trp including Kyn metabolites, microbiota-derived indoles and nicotinamide adenine dinucleotide (NAD +). We explore the potential of the Kyn/Trp ratio as a biomarker of inflammaging and discuss how intervening in Trp metabolism might extend health- and lifespan.

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          Origin and physiological roles of inflammation.

          Ruslan Medzhitov (2008)
          Inflammation underlies a wide variety of physiological and pathological processes. Although the pathological aspects of many types of inflammation are well appreciated, their physiological functions are mostly unknown. The classic instigators of inflammation - infection and tissue injury - are at one end of a large range of adverse conditions that induce inflammation, and they trigger the recruitment of leukocytes and plasma proteins to the affected tissue site. Tissue stress or malfunction similarly induces an adaptive response, which is referred to here as para-inflammation. This response relies mainly on tissue-resident macrophages and is intermediate between the basal homeostatic state and a classic inflammatory response. Para-inflammation is probably responsible for the chronic inflammatory conditions that are associated with modern human diseases.
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            Indoleamine 2,3 dioxygenase and metabolic control of immune responses.

            David Munn, Andrew L Mellor (2013)
            Sustained access to nutrients is a fundamental biological need, especially for proliferating cells, and controlling nutrient supply is an ancient strategy to regulate cellular responses to stimuli. By catabolizing the essential amino acid TRP, cells expressing the enzyme indoleamine 2,3 dioxygenase (IDO) can mediate potent local effects on innate and adaptive immune responses to inflammatory insults. Here, we discuss recent progress in elucidating how IDO activity promotes local metabolic changes that impact cellular and systemic responses to inflammatory and immunological signals. These recent developments identify potential new targets for therapy in a range of clinical settings, including cancer, chronic infections, autoimmune and allergic syndromes, and transplantation. Copyright © 2012 Elsevier Ltd. All rights reserved.
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              GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase.

              David Munn, Madhav D. Sharma, Babak Baban … (2005)
              Indoleamine 2,3 dioxygenase (IDO) catabolizes the amino acid tryptophan. IDO-expressing immunoregulatory dendritic cells (DCs) have been implicated in settings including tumors, autoimmunity, and transplant tolerance. However, the downstream molecular mechanisms by which IDO functions to regulate T cell responses remain unknown. We now show that IDO-expressing plasmacytoid DCs activate the GCN2 kinase pathway in responding T cells. GCN2 is a stress-response kinase that is activated by elevations in uncharged tRNA. T cells with a targeted disruption of GCN2 were not susceptible to IDO-mediated suppression of proliferation in vitro. In vivo, proliferation of GCN2-knockout T cells was not inhibited by IDO-expressing DCs from tumor-draining lymph nodes. IDO induced profound anergy in responding wild-type T cells, but GCN2-knockout cells were refractory to IDO-induced anergy. We hypothesize that GCN2 acts as a molecular sensor in T cells, allowing them to detect and respond to conditions created by IDO.
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                Author and article information

                Contributors
                Journal
                Journal ID (nlm-ta): Front Immunol
                Journal ID (iso-abbrev): Front Immunol
                Journal ID (publisher-id): Front. Immunol.
                Title: Frontiers in Immunology
                Publisher: Frontiers Media S.A.
                ISSN (Electronic): 1664-3224
                Publication date (Electronic): 30 October 2019
                Publication date Collection: 2019
                Volume: 10
                Electronic Location Identifier: 2565
                Affiliations
                [1] 1European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen , Groningen, Netherlands
                [2] 2Laboratory of Neurochemistry and Behavior, Department of Biomedical Sciences, Institute Born-Bunge, University of Antwerp , Antwerp, Belgium
                [3] 3Department of Neurology and Alzheimer Center, University Medical Center Groningen, University of Groningen , Groningen, Netherlands
                [4] 4Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen , Groningen, Netherlands
                [5] 5Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life Sciences (GELIFES), University of Groningen , Groningen, Netherlands
                [6] 6Department of Neurology, Memory Clinic of Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken , Antwerp, Belgium
                Author notes

                Edited by: Dietmar Fuchs, Innsbruck Medical University, Austria

                Reviewed by: Bruce James Brew, St. Vincent's Hospital Sydney, Australia; Maria Laura Belladonna, University of Perugia, Italy; Trevor William Stone, University of Oxford, United Kingdom

                *Correspondence: Peter P. De Deyn p.p.de.deyn@ 123456umcg.nl

                This article was submitted to Inflammation, a section of the journal Frontiers in Immunology

                Article
                DOI: 10.3389/fimmu.2019.02565
                PMC ID: 6833926
                PubMed ID: 31736978
                SO-VID: 83c8f4de-3f0b-46b7-b4ae-2043b1cbc033
                Copyright © Copyright © 2019 Sorgdrager, Naudé, Kema, Nollen and Deyn.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                Date received : 15 August 2019
                Date accepted : 16 October 2019
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 88, Pages: 8, Words: 6417
                Categories
                Subject: Immunology
                Subject: Mini Review

                ScienceOpen disciplines: Immunology
                Keywords: tryptophan,aging,inflammation,kynurenine,inflammaging,tryptophan 2,3-dioxygenase (tdo),indoleamine 2,3 dioxygenases (ido)
                Data availability:
                ScienceOpen disciplines: Immunology
                Keywords: tryptophan, aging, inflammation, kynurenine, inflammaging, tryptophan 2,3-dioxygenase (tdo), indoleamine 2,3 dioxygenases (ido)

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