scholarly journals Lithium inhibits tryptophan catabolism via the inflammation‐induced kynurenine pathway in human microglia

Glia ◽  
2021 ◽  
Author(s):  
Ria Göttert ◽  
Pawel Fidzinski ◽  
Larissa Kraus ◽  
Ulf Christoph Schneider ◽  
Martin Holtkamp ◽  
...  
Keyword(s):  
Kynurenine Pathway ◽  
Human Microglia ◽  
Tryptophan Catabolism

scholarly journals Lithium inhibits tryptophan catabolism via the inflammation-induced kynurenine pathway in human microglia

2020 ◽  
Author(s):  
Ria Göttert ◽  
Pawel Fidzinski ◽  
Larissa Kraus ◽  
Ulf Christoph Schneider ◽  
Martin Holtkamp ◽  
...  
Keyword(s):  
Chromatin Immunoprecipitation ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Kynurenine Pathway ◽  
Mrna Transcription ◽  
Human Microglia ◽  
Tryptophan Catabolism ◽  
Induced Pluripotent ◽  
Sb 216763 ◽  
Gsk3 Inhibitor

SummaryActivation of the kynurenine pathway may lead to depletion of the serotonin precursor tryptophan, which has been implicated in the neurobiology of depression. This study describes a mechanism whereby lithium inhibits inflammatory tryptophan breakdown. Upon activation, immortalized human microglia showed a robust increase in indoleamine-2,3-dioxygenase (IDO1) mRNA transcription, IDO1 protein expression, and activity. Further, chromatin immunoprecipitation verified enriched binding of both STAT1 and STAT3 to the IDO1 promoter. Lithium counteracted these effects, increasing inhibitory GSK3βS9 phosphorylation and reducing STAT1S727 and STAT3Y705 phosphorylation levels in activated cells. Experiments in primary human microglia and human induced pluripotent stem cell (hiPSC)-derived microglia corroborated lithium’s effects. Moreover, IDO activity was reduced by GSK3 inhibitor SB-216763 and STAT inhibitor nifuroxazide via downregulation of P-STAT1S727 and P-STAT3Y705. Our study demonstrates that lithium inhibits the inflammatory kynurenine pathway in the microglia compartment of the human brain.

PGE2-Independent Expression of Indoleamine 2,3-Dioxygenase-2 (IDO2) Supports the Tolerogenic Function of Monocyte-Derived Dendritic Cells,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3231-3231
Author(s):  
Sara Trabanelli ◽  
Antonio Curti ◽  
Darina Ocadlikova ◽  
Cecilia Evangelisti ◽  
Valentina Salvestrini ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
T Regulatory Cells ◽  
Immunological Tolerance ◽  
Kynurenine Pathway ◽  
Regulatory Pathways ◽  
Cell Functions ◽  
Ido1 Expression ◽  
Tryptophan Catabolism ◽  
Tolerogenic Function

Abstract Abstract 3231 The indoleamine 2,3-dioxygenases IDO1 and IDO2 participate in tryptophan catabolism along the kynurenine pathway and are specifically inhibited by 1-methyltryptophan (1-MT). IDO1 expression in dendritic cells (DCs) is upregulated by various maturation stimuli. In particular, PGE2 plays a crucial role in inducing IDO1-expressing DCs. While it is well established that IDO1-expressing DCs contribute to immunological tolerance by a number of mechanisms, little is known about the expression, function and regulation of IDO2 in DCs. Here we show that immature monocyte-derived DCs (Mo-DCs) express IDO2 which, like IDO1, is also upregulated upon maturation with a prostaglandin-E2 (PGE2)-containing cytokine cocktail. However, while IDO1 upregulation is strictly dependent on PGE2 during maturation, IDO2 expression level is not affected by PGE2. We show that IDO2 expressed by Mo-DCs is enzymatically active, producing L-kynurenine, and that this activity affects T-cell functions by inhibiting allogeneic and autologous T-cell proliferation and by inducing formation of a population of T regulatory cells (Tregs). Taken together, our findings establish different regulatory pathways for IDO2 and IDO1 in Mo-DCs, where IDO2 is functionally active, and they demonstrate that the tolerogenic function of Mo-DCs relies in part on PGE2-independent expression of IDO2. Disclosures: Metz: New Link Genetics Corporation: Employment. Prendergast:New Link Genetics Corporation: Employment.

scholarly journals Reversal of the Kynurenine Pathway of Tryptophan Catabolism May Improve Depression in ART-Treated HIV-Infected Ugandans

2014 ◽  
Vol 65 (4) ◽  
pp. 456-462 ◽  
Author(s):  
Priscilla Martinez ◽  
Alexander C. Tsai ◽  
Conrad Muzoora ◽  
Annet Kembabazi ◽  
Sheri D. Weiser ◽  
...  
Keyword(s):  
Kynurenine Pathway ◽  
Tryptophan Catabolism

scholarly journals MO006CHANGES IN THE KYNURENINE PATHWAY LEAD TO ALTERATIONS IN NAD BALANCE AND BIOENERGETICS PARAMETERS IN GLOMERULAR CELLS IN VITRO AND CONTRIBUTE TO PROTEINURIA IN A ZEBRAFISH  MODEL*

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Patricia Bolanos-Palmieri ◽  
Ahmed Kotb ◽  
Heiko Schenk ◽  
Heike Bähre ◽  
Patricia Schroder ◽  
...  
Keyword(s):  
Mitochondrial Membrane ◽  
De Novo ◽  
Kynurenine Pathway ◽  
Mass Spectrometry Analysis ◽  
Bioactive Metabolites ◽  
Enzymatic Function ◽  
Wide Range ◽  
Tryptophan Catabolism

Abstract Background and Aims Tryptophan catabolism is carried out by the enzymes of the kynurenine pathway leading to the de novo synthesis of NAD and the production of a series of bioactive metabolites. Kynurenine 3-Monooxigenase (KMO) is a key component of this pathway and it is one of the enzymes responsible for the degradation of kynurenine. The kynurenine metabolites participate in various cellular processes, so systemic dysregulation of tryptophan metabolism, marked by increased kynurenine in the circulation, has been linked to the onset and severity of a wide range of pathologies, such as chronic kidney disease and associated co-morbidities. Since the enzymes of the kynurenine pathway are expressed in the kidney and the metabolites are cleared in the urine, we aim to describe the effects of changes in tryptophan catabolism on glomerular cells, both in vitro and in vivo. Method Modulation of KMO expression or enzymatic function was performed in a transgenic zebrafish line that allows for the monitoring of a fluorescently labelled protein in the circulation as an indicator for proteinuria. Morpholinos targeting three enzymes of the kynurenine pathway were injected into fish embryos, leading to a knockdown of Afmid, Kmo and Kynu. Additionally, dechorionated larvae were treated with a Kmo inhibitor administered via the embryo rearing media, starting at 48hpf. In all cases at 96hpf, circulating fluorescent protein levels were determined, larval phenotype was scored based on the severity of the edema, and samples were collected for metabolite analysis or fixed and prepared for imaging. Since the kynurenine pathway results in the de novo production of NAD, and the enzyme KMO is located in the outer mitochondrial membrane, cultured murine parietal epithelial cells as well as immortalized human and mouse podocytes were incubated with a KMO inhibitor. Changes in NAD+ and NADH, as well as alterations in the mitochondrial membrane polarization were assessed. Additionally, the oxygen consumption rate was measured in order to determine if KMO inhibition leads to changes in the bioenergetics parameters of glomerular cells in vitro. Results The modification of Afmid, Kmo and Kynu expression levels by morpholino mediated knockdown or inhibition of Kmo lead to the accumulation of upstream kynurenine metabolites in the treated larvae, as was confirmed by mass spectrometry analysis. Following our previous results, alteration of the kynurenine pathway led to the development of yolk sac edema, pericardial effusion and loss of protein from the circulation, accompanied by an enlargement of the Bowman’s space and changes in nephrin expression in the glomerulus of the treated larvae. Under cell culture conditions, KMO inhibition in immortalized podocytes led to a reduction in cell size and focal adhesion proteins (podocalyxin). The NAD+/NADH ratio as well as mitochondrial membrane polarity were also altered. Additionally, changes in spare respiratory capacity, coupling efficiency and proton leak suggest that alterations in the kynurenine pathway might impair the cell’s ability to adapt its bioenergetic profile in response to stress. Conclusion Taken together these results suggest that the modulation of tryptophan catabolism through the kynurenine pathway may contribute to maintaining the structural integrity of glomerular cytoskeleton as well a flexible energy metabolism in podocytes. Moreover, the results from our in vivo model also suggest that imbalances in kynurenine metabolites might ultimately impact the function of the glomerular filtration barrier.

scholarly journals TARGETING TRYPTOPHAN-KYNURENINE METABOLISM TO EXTEND LIFESPAN AND TREAT AGE-ASSOCIATED DISEASE

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S616-S616
Author(s):  
George L Sutphin ◽  
George L Sutphin
Keyword(s):  
Cardiovascular Disease ◽  
Mechanistic Model ◽  
Kynurenine Pathway ◽  
C Elegans ◽  
Single Target ◽  
Extended Lifespan ◽  
Tryptophan Catabolism ◽  
Major Route ◽  
Kynurenine Metabolism ◽  
Hydroxyanthranilic Acid

Abstract The kynurenine pathway, the major route for tryptophan catabolism, becomes dysregulated with age and in many age-associated pathologies in humans. Interventions targeting kynurenine metabolism are being pursued for neurodegeneration, cardiovascular disease, and chronic kidney disease. By manipulating kynurenine pathway enzymes and metabolites, we have extended lifespan up to 40% in Caenorhabditis elegans. Our most promising single target is the metabolite 3-hydroxyanthranilic acid dioxygenase (3HAA). Elevating physiological 3HAA by directly supplementing 3HAA or inhibiting the enzyme 3HAA dioxygenase (HAAO) extends worm lifespan by ~30% while reducing oxidative stress by directly degrading hydrogen peroxide. In rodents, anti-inflammatory activity of 3HAA improves outcomes in models of cardiovascular disease, asthma, and autoimmune encephalomyelitis. We are now beginning to validate our C. elegans work in mice and investigating a mechanistic model in which 3HAA acts to extend healthy lifespan by slowing age-associated accumulation of oxidative damage and repressing chronic inflammation.

Ischemic Stroke and Kynurenines: Medicinal Chemistry Aspects

2019 ◽  
Vol 25 (42) ◽  
pp. 5945-5957 ◽  
Author(s):  
Péter Hertelendy ◽  
József Toldi ◽  
Ferenc Fülöp ◽  
László Vécsei
Keyword(s):  
Ischemic Stroke ◽  
Glutamate Release ◽  
Developed Countries ◽  
Kynurenine Pathway ◽  
Permanent Disability ◽  
Clinical Investigations ◽  
Tryptophan Catabolism ◽  
Nmda Glutamate Receptor ◽  
Causes Of Mortality ◽  
Nmda Glutamate Receptor Antagonist

Ischemic stroke is one of the leading causes of mortality and permanent disability in developed countries. Stroke induces massive glutamate release, which in turn causes N-Methyl-D-aspartate (NMDA) receptor over-excitation and thus, calcium overload in neurons leading to cell death via apoptotic cascades. The kynurenine pathway is a complex enzymatic cascade of tryptophan catabolism, generating various neuroactive metabolites. One metabolite, kynurenic acid (KYNA), is a potent endogenous NMDA glutamate receptor antagonist, making it a possible therapeutic tool to decrease excitotoxicity and neuroinflammation. Recently, clinical investigations have shown that during the acute phase of ischemic stroke, kynurenine pathway is activated and peripheral levels of metabolites correlated with worse outcome. In this review, we set out to summarize the current literature on the connection of the kynurenine pathway and ischemic stroke and set a course for future investigations and potential drug development.

scholarly journals Kynurenine Monooxygenase Expression and Activity in Human Astrocytomas

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2028
Author(s):  
Gustavo Ignacio Vázquez Cervantes ◽  
Benjamín Pineda ◽  
Daniela Ramírez Ortega ◽  
Alelí Salazar ◽  
Dinora Fabiola González Esquivel ◽  
...  
Keyword(s):  
Protein Expression ◽  
Mrna Expression ◽  
Cell Lines ◽  
Kynurenine Pathway ◽  
Primary Brain Tumor ◽  
Rate Limiting Step ◽  
Tryptophan Catabolism ◽  
Tryptophan Oxidation ◽  
Rate Limiting ◽  
Expression And Activity

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. The enzyme indoleamine-2,3-dioxygenase (IDO), which participates in the rate-limiting step of tryptophan catabolism through the kynurenine pathway (KP), is associated with poor prognosis in patients with GBM. The metabolites produced after tryptophan oxidation have immunomodulatory properties that can support the immunosuppressor environment. In this study, mRNA expression, protein expression, and activity of the enzyme kynurenine monooxygenase (KMO) were analyzed in GBM cell lines (A172, LN-18, U87, U373) and patient-derived astrocytoma samples. KMO mRNA expression was assessed by real-time RT-qPCR, KMO protein expression was evaluated by flow cytometry and immunofluorescence, and KMO activity was determined by quantifying 3-hydroxykynurenine by HPLC. Heterogenous patterns of both KMO expression and activity were observed among the GBM cell lines, with the A172 cell line showing the highest KMO expression and activity. Higher KMO mRNA expression was observed in glioma samples than in patients diagnosed with only a neurological disease; high KMO mRNA expression was also observed when using samples from patients with GBM in the TCGA program. The KMO protein expression was localized in GFAP+ cells in tumor tissue. These results suggest that KMO is a relevant target to be explored in glioma since it might play a role in supporting tumor metabolism and immune suppression.

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