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TLR ligands trigger transcriptional activation of STAT-1 and NF-κB, and then induce IDO mRNA. Although AHR forms complex with STAT-1 and NF-κB in macrophages under pro-inflammatory cytokines production, whether this complex is appeared in DC or required for IDO expression is not known. Induced IDO mRNA may be controlled by miR-203 (not investigated), and the activity or amount of IDO protein is regulated at post-translational modification such as nitration of Tyr and ubiquitin ligation. Kynurenine catalyzed by IDO induces tolerance via regulating the balance of TH1, TH17, Tr1, and Treg. Kynurenine may activate the AHR for IDO induction with autocrine manner, and form AHR/Kynurenine positive-feedback loop.

TLR ligands trigger transcriptional activation of STAT-1 and NF-κB, and then induce IDO mRNA. Although AHR forms complex with STAT-1 and NF-κB in macrophages under pro-inflammatory cytokines production, whether this complex is appeared in DC or required for IDO expression is not known. Induced IDO mRNA may be controlled by miR-203 (not investigated), and the activity or amount of IDO protein is regulated at post-translational modification such as nitration of Tyr and ubiquitin ligation. Kynurenine catalyzed by IDO induces tolerance via regulating the balance of TH1, TH17, Tr1, and Treg. Kynurenine may activate the AHR for IDO induction with autocrine manner, and form AHR/Kynurenine positive-feedback loop.

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Aryl hydrocarbon receptor (AHR) is thought to be a crucial factor in the regulation of immune responses. Many AHR-mediated immunoregulatory mechanisms have been discovered, and this knowledge may enhance our understanding of the molecular pathogenesis of autoimmune inflammatory syndromes such as collagen-induced arthritis, experimental autoimmune e...

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... 50 AhR is a ubiquitous receptor for aromatic endogenous and exogenous molecules acting as a transcription factor once activated and is involved in immune-regulatory mechanisms. 43,51,52 Kynurenic acid was demonstrated to be a ligand of AhR with an affinity of the low micromolar range and a high stability 51,53 allowing to the activation of AhR under-inflammatory conditions and inducing indole 2,3-diamine oxygenase (IDO) phosphorylation and transcription. 54 IDO, the first enzyme that catalyzes the first steps in the kynurenine pathways, is well-known to promote immune-regulatory mechanisms and tolerance in solid organ transplantation. ...
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Background Operational tolerance is the holy grail in solid organ transplantation. Previous reports showed that the urinary compartment of operationally tolerant recipients harbor a specific and unique profile. We hypothesized that spontaneous tolerant kidney transplanted recipients (KTR) would have a specific urinary metabolomic profile associated to operational tolerance. Methods We performed metabolomic profiling on urine samples from healthy volunteers, stable KTR under standard and minimal immunosuppression and spontaneous tolerant KTR using liquid chromatography in tandem with mass spectrometry. Supervised and unsupervised multivariate computational analyses were used to highlight urinary metabolomic profile and metabolite identification thanks to workflow4metabolomic platform. Findings The urinary metabolome was composed of approximately 2700 metabolites. Raw unsupervised clustering allowed us to separate healthy volunteers and tolerant KTR from others. We confirmed by two methods a specific urinary metabolomic signature in tolerant KTR mainly driven by kynurenic acid independent of immunosuppressive drugs, serum creatinine and gender. Interpretation Kynurenic acid and tryptamine enrichment allowed the identification of putative pathways and metabolites associated with operational tolerance like IDO, GRP35 and AhR and indole alkaloids. Funding This study was supported by the ANR, IRSRPL and CHU de Nantes.
... The latter is the intermediate for the synthesis of either quinolinic acid or picolinic acid [1], the former being the precursor of NAD (nicotinamide adenine dinucleotide) and known to promote the formation of reactive oxygen species with a proinflammatory profile through the agonistic action on NMDA receptors [2], while the latter is known to have protective properties by contrasting the activity of quinolinic acid on the same receptor [3]. KYN is an important neuromodulator that targets the aryl hydrocarbon receptor, which represents a crucial factor in the regulation of immune responses [4]. ...
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L-Kynurenine (KYN) and kynurenic acid (KYNA) are products of the metabolism of L-tryptophan (TRP) in the central nervous system of animals, but they are not commonly found in plants. In particular, KYNA is known for its interesting pharmacological properties (anti-oxidative, anti-inflammatory, hypolipidemic, and neuroprotective), which suggest a potential functional food ingredient role. The three compounds were identified in samples of Cannabis sativa L. by means of high-performance liquid chromatography coupled to high-resolution mass spectrometry using an untargeted metabolomics approach. Their concentrations were evaluated using a targeted metabolomics method in three organs of the plant (roots, stem, and leaves) in soil at two different growth stages and in hydroponics conditions. The distribution of TRP, KYN and KYNA was found tendentially higher in leaves compared to stem and roots and changed over time. Moreover, the levels of KYNA found in this study are unprecedentedly high compared to those found so far in other plant species, suggesting that Cannabis sativa L. could be a promising alternative source of this metabolite.
... Recent work showed that IDO induction depends on activation of the Aryl hydrocarbon receptor (AhR) (Nguyen et al. 2014). AhR is a ligand-activated member of transcription factors with Kynurenine and Kynurenic Acid as a potent internal AhR agonists (Kerkvliet 2012;Sogawa and Fujii-Kuriyama 1997). ...
... Although not significant, the decreased levels of AhR immediately after CPET might be of importance as recent findings have revealed induction of IDO depends on AhR expression (Nguyen et al. 2014). Consequently, IDO-mediated Tryptophan catabolism and Kynurenine formation which is an AhR agonist is an important immunoregulatory mechanism underlying immunosuppression and tolerance (Park et al. 2019). ...
... The similar expression pattern of both AhR and IDO is indicative of the inter-dependent relationship between them. The restored levels of AhR and IDO after 1 h of CPET can indicate to the AhR and IDO feedback loop (as discussed in Introduction section (Nguyen et al. 2014)), as IDO levels correspond to the AhR expression pattern forming the AhR/IDO axis. ...
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... Indole compounds were reported as aryl hydrocarbon receptor (AHR) ligands. Recent studies have demonstrated that IDO induction depends on AHR expression [86]. GvHD development is associated with a decrease in indole compounds that could then limit IDO induction. ...
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... In this manner, increased synthesis of KYN, mainly by IDO, suppresses the immune system response. It causes the inactivation and apoptosis of TH1 and effector T cells, as well as activation of immunosuppressive T regulatory cells, preventing an excessive immune response [43,44,46,244,245]. The excessive activation of AhR, caused by elevated concentrations of KYN and its metabolites, increases oxidative stress levels, proinflammatory cytokine release, and as a result enhances cell aging and death rate [32,42,43,46,245]. ...
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The tryptophan (TRP)-kynurenine (KYN) metabolic pathway is a main player of TRP metabolism through which more than 95% of TRP is catabolized. The pathway is activated by acute and chronic immune responses leading to a wide range of illnesses including cancer, immune diseases, neurodegenerative diseases and psychiatric disorders. The presence of positive feedback loops facilitates amplifying the immune responses vice versa. The TRP-KYN pathway synthesizes multifarious metabolites including oxidants, antioxidants, neurotoxins, neuroprotectants and immunomodulators. The immunomodulators are known to facilitate the immune system towards a tolerogenic state, resulting in chronic low-grade inflammation (LGI) that is commonly present in obesity, poor nutrition, exposer to chemicals or allergens, prodromal stage of various illnesses and chronic diseases. KYN, kynurenic acid, xanthurenic acid and cinnabarinic acid are aryl hydrocarbon receptor ligands that serve as immunomodulators. Furthermore, TRP-KYN pathway enzymes are known to be activated by the stress hormone cortisol and inflammatory cytokines, and genotypic variants were observed to contribute to inflammation and thus various diseases. The tryptophan 2,3-dioxygenase, the indoleamine 2,3-dioxygenases and the kynurenine-3-monooxygenase are main enzymes in the pathway. This review article discusses the TRP-KYN pathway with special emphasis on its interaction with the immune system and the tolerogenic shift towards chronic LGI and overviews the major symptoms, pro- and anti-inflammatory cytokines and toxic and protective KYNs to explore the linkage between chronic LGI, KYNs, and major psychiatric disorders, including depressive disorder, bipolar disorder, substance use disorder, post-traumatic stress disorder, schizophrenia and autism spectrum disorder.
... An elevated KYNA level has been observed in the CSF of patients with SCZ, as KMO is responsible for the conversion of L-KYN to 3-HK, based on the fact that the amount of L-KYN available for KYNA synthesis decreases; thus, the increase in KYNA in SCZ is due to increased KYN and overexpression of KAT, irrespective of changes in KMO [96]. L-KYN has been reported to support the regulatory T-cells and tumor formation through the AhR as well as the activation of the adenylate-and guanylate-cyclase pathways [27,97,98]. Presumably, an increase in kynurenine metabolism via over-expression of KMO may provide a protection against tumorigenesis (Boros and Vécsei, 2019). ...
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The tryptophan (TRP)-kynurenine (KYN) metabolic pathway is a main player of TRP metabolism through which more than 95% of TRP is catabolized. The pathway is activated by acute and chronic immune responses leading to a wide range of illnesses including cancer, immune diseases , neurodegenerative diseases, and psychiatric disorders. The TRP-KYN pathway synthesizes multifarious metabolites including oxidants, antioxidants, neurotoxins, neuroprotectants, and im-munomodulators. The immunomodulators are known to facilitate the immune system towards a tolerogenic state, resulting in chronic low-grade inflammation (LGI) that is commonly present in obesity, poor nutrition, exposer to chemicals or allergens, prodromal stage of various illnesses, and chronic diseases. KYN, kynurenic acid, xanthurenic acid, and cinnabarinic acid are aryl hydrocarbon receptor ligands that serve as immunomodulators. Furthermore, TRP-KYN pathway enzymes are known to be activated by the stress hormone cortisol and inflammatory cytokines, and genotypic variants were observed to contribute to inflammation and thus various diseases. The tryptophan 2,3-dioxygenase, the indoleamine 2, 3-oxygenases, and the kynurenine-3-monooxygenase are main enzymes in the pathway. This review article discusses the TRP-KYN pathway with special emphasis on its interaction with the immune system and the tolerogenic shift towards chronic LGI and overviews the major symptoms, pro-and anti-inflammatory cytokines, and toxic and protective KYNs to explore the linkage between chronic LGI, KYNs, and major psychiatric, including depressive disorder , bipolar disorder, substance use disorder, post-traumatic stress disorder, schizophrenia, and autism spectrum disorder.
... This molecule is an agonist of AhR, a crucial factor in the immune response regulation that exerts its roles through different immunoregulatory mechanisms. In fact, when activated, AhR is capable of inhibiting the production of several proinflammatory cytokines and of controlling the generation of regulatory T (Treg) cells and/or T helper 17 (Th17) cells in mouse models of autoimmune diseases [39]. The finding of possible kynurenine participation in a positive feedback loop in AhR signalling paves the way to a probable use of kynurenine as an immunoregulatory drug. ...
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... During inflammation, the expression of TDO is reduced and IDO1 expression is increased. Once IDO1 is activated upon signaling from cytokines such as IFN-γ, TNFα, prostaglandins and lipopolysaccrides, it converts tryptophan into N-formylkynurenine, followed by a rapid transformation into Kyn, the first stable catabolite in the pathway [5,39,40]. Kyn is then acted upon by various enzymes in a tissue-dependent manner and produces downstream neuroactive and immunoactive metabolites which regulate immune cell activity [41]. ...
... This alteration in the indolic pathway can lead to an increased inflammatory response via TNFα, IL-1β, and IL-6 in colon carcinogenesis, subsequently altering AhR activity [109]. AhR activation is reduced in diseases including IBD, liver disease, metabolic syndrome, autoimmune disease, and cancer, suggesting that alteration in Trp metabolism or indole production my contribute to AhR dysfunction [39,54,55,79]. Fecal samples from individuals with metabolic syndrome, obesity, Type-2 diabetes, and chronic intestinal inflammation also have significantly lower levels of microbial Trp metabolites, potentially contributing to reduced AhR activation. ...
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Full-text available
Tryptophan metabolism, via the kynurenine (Kyn) pathway, and microbial transformation of tryptophan to indolic compounds are fundamental for host health; both of which are altered in colon carcinogenesis. Alterations in tryptophan metabolism begin early in colon carcinogenesis as an adaptive mechanism for the tumor to escape immune surveillance and metastasize. The microbial community is a key part of the tumor microenvironment and influences cancer initiation, promotion and treatment response. A growing awareness of the impact of the microbiome on tryptophan (Trp) metabolism in the context of carcinogenesis has prompted this review. We first compare the different metabolic pathways of Trp under normal cellular physiology to colon carcinogenesis, in both the host cells and the microbiome. Second, we review how the microbiome, specifically indoles, influence host tryptophan pathways under normal and oncogenic metabolism. We conclude by proposing several dietary, microbial and drug therapeutic modalities that can be utilized in combination to abrogate tumorigenesis.
... During inflammation, the expression of TDO is reduced and IDO1 expression is increased. Once IDO1 is activated upon signaling from cytokines such as IFN-γ, TNFα, prostaglandins and lipopolysaccrides, it converts tryptophan into N-formylkynurenine, followed by a rapid transformation into Kyn, the first stable catabolite in the pathway [5], [39], [40]. Kyn is then acted upon by various enzymes in a tissue-dependent manner and produces downstream neuroactive and immunoactive metabolites which regulate immune cell activity [41]. ...
... This alteration in the indolic pathway can lead to an increased inflammatory response via TNFα, IL-1β, and IL-6 in colon carcinogenesis, subsequently altering AhR activity [112]. AhR activation is reduced in diseases including IBD, liver disease, metabolic syndrome, autoimmune disease, and cancer, suggesting that alteration in Trp metabolism or indole production my contribute to AhR dysfunction [39], [55], [56], [82]. Fecal samples from individuals with metabolic syndrome, obesity, Type-2 diabetes, and chronic intestinal inflammation also have significantly lower levels of microbial Trp metabolites, potentially contributing to reduced AhR activation. ...
Preprint
Tryptophan metabolism, via the kynurenine (Kyn) pathway, and microbial transformation of tryptophan to indolic compounds, are fundamental for host health; both of which are altered in colon carcinogenesis. Alterations in tryptophan metabolism begin early in colon carcinogenesis as an adaptive mechanism for the tumor to escape immune surveillance and metastasize. The microbial community is a key part of the tumor microenvironment and influences cancer initiation, promotion and treatment response. A growing awareness of the impact of the microbiome on tryptophan (Trp) metabolism in the context of carcinogenesis has prompted this review. We first compare the different metabolic pathways of Trp under normal cellular physiology to colon carcinogenesis, in both the host cells and the microbiome. Second, we review how the microbiome, specifically indoles, influence host tryptophan pathways under normal and oncogenic metabolism. We conclude by proposing several dietary, microbial and drug therapeutic modalities that can be utilized in combination to abrogate tumorigenesis.