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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.
Source publication
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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CD4⁺ regulatory T (Treg) cells and T-helper 17 (Th17) cells have been shown to have important roles in rheumatoid arthritis (RA). In our previous study, it was demonstrated that artesunate was able to alter the Treg/Th17 ratio in patients with RA; however, the underlying mechanisms remain unclear. The present study established a male Sprague Dawley...
Citations
... In addition, the IFN-γ-mediated mechanisms and those mediated by TNF-α, IL-1β, and toll-like receptor (TLR) agonists such as LPS may act synergistically to enhance the induction of IDO [37][38][39][40][41]. Another known mechanism of IDO activation is through the aryl hydrocarbon receptor (AhR), which is widely distributed in the brain and brain stem [42]. AhRs can induce IDO by binding to KYN, generating a positive feedback loop (reviewed in: [43]). ...
Background:
Acute bacterial meningitis (ABM) causes excessive activation of N-methyl-D-aspartate receptors (NMDAr), leading to cortical and hippocampal neuron death. As opposite, enteroviral meningitis is more frequently benign. The kynurenine (KYN) pathway is the major catabolic route of tryptophan (TRP) and some of its metabolites are agonists or antagonists of NMDAr.
Methods:
In order to investigate the pathogen-specific patterns of KYN pathway modulation in the central nervous system of children with acute meningococcal (MM), pneumococcal (PM) or enteroviral (VM) meningitis, the cerebrospinal fluid (CSF) concentrations of TRP, KYN, kynurenic acid (KYNA) and quinolinic acid (QUINA) were evaluated by ultra-high performance liquid chromatography (uHPLC) coupled to mass spectrometry. In addition, CSF levels of IL-6, IL-10 and TNF-α were quantified by multi-analyte flow assay. The data was mined and integrated using statistical and machine learning methods.
Results:
The three forms of meningitis investigated herein up-regulated the neurotoxic branch of the KYN pathway within the intrathecal space. However, this response, represented by the concentration of QUINA, was six and nine times higher in PM patients compared to MM or VM, respectively. CSF levels of IL-6, TNF-α, and IL-10 were increased in MM and PM patients when compared to controls. In VM, CSF IL-6 and IL-10, but not TNF-α were increased compared to controls, although not reaching the high levels found in bacterial meningitis. No correlation was found between the concentrations or the ratios of any pair of KYN metabolites and any cytokine or standard cytochemical parameter tested.
Conclusions:
CNS infection with meningococci, pneumococci, and enteroviruses intrathecally activate the KYN pathway, favoring its neurotoxic branch. However, in PM, higher CSF levels of QUINA, compared to MM and VM, may contribute to its poorer neurologic outcome.
... As shown on Figure 5A, kynurenine level was statistically higher in blood than BM (1.54 ± 0.13 vs 0.87 ± 0.09; p = 0.0078 Aryl hydrocarbon receptor (AHR) is claimed to be a crucial factor in the regulation of immune responses, including the IDO role for the development of Treg. 36 AHR mediates cellular responses to kynurenine by binding in the nucleus ...
... AHR nucleus translocator (ARNT) followed by other genes including cytochromes P450 (CYP). 36 As kynurenine analysis has displayed higher activity or concentration of IDO enzyme in peripheral blood, in the last set of experiments, we have performed transcriptomic analyses of selected genes, which are involved in IDO and AHR-pathways using RNA-seq in monocytes from RA patients compared to healthy controls ( Figure 5B). Fold change of the main enzymes responsible for tryptophan degradation in IDO-pathway like IDO-1, kynurenine 3-monooxygenase (KMO) or kynurenine aminotransferase (KAT) indicate their higher expression in RA monocytes as compared to HC. ...
Background:
Rheumatoid arthritis (RA) is a chronic autoimmune disease with systemic inflammation finally resulting in damaged joints. One of the RA development models suggests bone marrow (BM) as a place of inflammation development further leading to disease progression. We aimed to investigate the potential of CTLA-4-Fc molecule in inducing tolerogenic milieu in BM measured as indoleamine 2,3-dioxygenase (IDO) expression, CD4+Foxp3+ Treg induction, and T cell activation control. The expression of IDO-pathway genes was also examined in monocytes to estimate the tolerogenic potential in the periphery.
Methods:
Bone marrow mononuclear cells (BMMC) were stimulated by pro-inflammatory cytokines and CTLA-4-Fc. Next IDO expression, CD4+CD69+ and CD4+Foxp3+ percentage were estimated by PCR and FACS staining, respectively. Enzymatic activity of IDO was confirmed by HPLC in BM plasma and blood plasma. Genes expressed in IDO-pathway were analyzed by NGS in peripheral monocytes isolated from RA patients and healthy controls.
Results:
We found that CTLA-4-Fc and IFN-γ stimulation results in IDO production by BMMC. CTLA-4-Fc induced tryptophan catabolism can inhibit mitogen-induced CD4+ T cells activation without influencing CD8+ cells, but did not control CD25 nor Foxp3 expression in BM cells. Significantly higher expression of selected IDO-pathway genes was detected on peripheral monocytes isolated from RA as compared to healthy controls.
Conclusion:
This study sheds light on some immunosuppression aspects present or induced in BM. The potential of IDO-mediated pathways were confirmed in the periphery, what may represent the promising candidates for therapeutic strategies in RA.
... For example, L-tryptophan (Trp) is an important component of protein, and can be converted into a variety of substances (such as serotonin, melatonin, indole, kynurenine) as a metabolic substrate. It plays an important role in the onset of neurological diseases and immune regulation such as intestinal tolerance, balance between intestinal microbiota, hinder depression, chronic fatigue syndrome and physical mobility disorder (110)(111)(112)(113); Endogenous Trp metabolites (kynurenines, serotonin, and melatonin), and bacterial Trp metabolites (indole, indolic acid, skatole, and tryptamine) also have profound effects on gut microbial composition, microbial metabolism, the host's immune system, the host-microbiome interface, and host immune system-intestinal microbiota interactions (114); Aromatic amino acids are metabolized by gut microbes and their products can serve as signaling molecules in host physiology (115). ...
A large number of studies have proved that biological metabolic phenotypes exist objectively and are gradually recognized by humans. Gut microbes affect the host’s metabolic phenotype. They directly or indirectly participate in host metabolism, physiology and immunity through changes in population structure, metabolite differences, signal transduction and gene expression. Obtaining comprehensive information and specific identification factors associated with gut microbiota and host metabolic phenotypes has become the focus of research in the field of gut microbes, and it has become possible to find new and effective ways to prevent or treat host metabolic diseases. In the future, precise treatment of gut microbes will become one of the new therapeutic strategies. This article reviews the content of gut microbes and carbohydrate, amino acid, lipid and nucleic acid metabolic phenotypes, including metabolic intermediates, mechanisms of action, latest research findings and treatment strategies, which will help to understand the relationship between gut microbes and host metabolic phenotypes and the current research status.
... It is also well established that the indoleamine 2,3-dioxygenase (IDO) enzyme significantly contributes to immune regulation by depleting TRP and producing kynurenine (KYN) (11,12). A link between the aryl hydrocarbon receptor and IDO is identified in the expansion of Th17 and regulatory T cells, which plays a significant role in various autoimmune disorders and cancer (13,14). Kynurenic acid (KYNA), which is a metabolite produced through the KP, acts as a neuroprotective agent, while quinolinic acid (QUIN) is an established neurotoxic agent (15)(16)(17)(18)(19)(20). ...
Background
Multiple sclerosis (MS) is a debilitating neurodegenerative disorder characterized by axonal damage, demyelination, and perivascular inflammatory lesions in the white matter of the central nervous system (CNS). Kynurenine pathway (KP), which is the major route of tryptophan (TRP) metabolism, generates a variety of neurotoxic as well as neuroprotective compounds, affecting MS pathology and the severity of impairments. Alterations in KP have been described not only in MS, but also in various psychiatric and neurodegenerative diseases. The purpose of this systematic review is to investigate the previously reported dysregulation of KP and differences in its metabolites and enzymes in patients with MS compared to healthy control subjects.
Method
Electronic databases of PubMed, Scopus, Cochrane Database of Systematic Reviews, and Web of Science were searched to identify studies measuring concentrations of KP metabolites and enzymes in MS patients and control subjects. The following metabolites and enzymes implicated in the KP were investigated: TRP, kynurenine (KYN), kynurenic acid (KYNA), quinolinic acid (QUIN), picolinic acid (PIC), hydroxyindoleacetic acid (HIAA), indoleamine 2,3-dioxygenase (IDO), kynurenine aminotransferase (KAT), and their related ratios.
Result
Ten studies were included in our systematic review. Our review demonstrates that IDO expression is reduced in the peripheral blood mononuclear cells (PBMCs) of MS patients compared to healthy controls. Also, increased levels of QUIN and QUIN/KYNA in the serum and cerebrospinal fluid (CSF) of MS patients is observed. Differences in levels of other metabolites and enzymes of KP are also reported in some of the reviewed studies, however there are discrepancies among the included reports.
Conclusion
The results of this investigation suggest a possible connection between alterations in the levels of KP metabolite or enzymes and MS. QUIN levels in CSF were higher in MS patients than in healthy controls, suggesting that QUIN may be involved in the pathogenesis of MS. The data indicate that differences in the serum/blood or CSF levels of certain KP metabolites and enzymes could potentially be used to differentiate between MS patients and control subjects.
... 25,26 The IDO1-AHR pathway is particularly important for maintaining barrier organ integrity by preventing the immune system from becoming hyperactivated or promoting tissue repair after those organs are damaged by infection or injury. 27,28 AHR is a ligand-activated nuclear transcription factor. AHR ligands are a variety of small molecules derived from diet, microorganisms, metabolism, and xenobiotic toxic chemicals. ...
... 30,31 During immune responses, L-Kyn is released by DCs and epithelial cells and acts on AHR in an autocrine and/or paracrine fashion. 27,32 Even though AHR is involved in the differentiation of Th17 cells in some cases. 33,34 it plays an indispensable role in driving FoxP3 + regulatory T-cell (Treg) differentiation. ...
Preconditioning of mesenchymal stem/stromal cells (MSCs) with the inflammatory cytokine IFN-γ enhances not only their immunosuppressive activity but also their expression of HLA and proinflammatory genes. We hypothesized that prevention of the upregulation of inflammatory cytokines and HLA molecules in IFN-γ-primed MSCs would render these cells more immunosuppressive and less immunogenic. In this study, we discovered the following findings supporting this hypothesis: 1) activated human T cells induced the expression of IDO1 in MSCs via IFN-γ secretion and those MSCs in turn inhibited T-cell proliferation in an AHR-dependent fashion; 2) there was no difference in the expression of IDO1 and HLA-DR in MSCs after priming with a low dose (25 IU/ml) versus a high dose (100 IU/ml) of IFN-γ; 3) the transient addition of bortezomib, a proteasome inhibitor, to culture MSCs after IFN-γ priming decreased the expression of HLA-DR, inflammatory cytokine genes and Vcam1 while increasing the expression of IDO1 and the production of L-kynurenine; finally, MSCs primed with a combination of a low dose of IFN-γ and bortezomib were more effective in inhibiting Th17-mediated idiopathic pneumonia syndrome (IPS) and chronic colitis than unprimed MSCs. Our results suggest that bortezomib significantly eliminates the unfavorable effects of IFN-γ priming of MSCs (increased expression of MHC molecules and inflammatory cytokines and cell aggregation genes) and simultaneously increases their immunosuppressive activity by upregulating IDO1. Taken together, our newly established MSC priming method may contribute to MSC-based cell therapy for inflammatory diseases.
... Subsequently, KYN is degraded to kynurenic acid (KYNA), 3-hydroxykynurenine (3-HKYN) and anthranilic acid (ATA) by kynurenine aminotransferase (KAT), kynurenine 3-monooxygenase and kynureninase, respectively (Figure 1a). The KYN pathway has been implicated in the pathophysiology of several diseases including neurodegenerative disorders [1], cancer, infection [2], autoimmune disorders [3] and psychiatric disorders [4]. Moreover, TRP is also the obligatory substrate for the production of several important bioactive neurotransmitters and neurotransmitter-like compounds. ...
L-Tryptophan (TRP) metabolites and related biomarkers play crucial roles in physiological functions, and their imbalances are implicated in central nervous system pathologies and neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, Parkinson’s disease, schizophrenia and depression. The measurement of TRP metabolites and related biomarkers possesses great potential to elucidate the disease mechanisms, aid preclinical drug development, highlight potential therapeutic targets and evaluate the outcomes of therapeutic interventions. An effective, straightforward, sensitive and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the simultaneous determination of 24 TRP-related compounds in miniaturised murine whole blood samples. Sampling and sample pretreatment miniaturisation were achieved thanks to the development of a volumetric dried blood microsampling approach. Volumetric absorptive microsampling (VAMS) allows the accurate sampling of microvolumes of blood with advantages including, but not limited to, minimal sampling invasiveness, logistical improvements, method sustainability in terms of solvents and energy consumption, and improvement of animal studies in the framework of the 3Rs (Replacement, Reduction and Refinement) principles on animal welfare. The VAMS-LC-MS/MS method exhibited good selectivity, and correlation coefficient values for the calibration curves of each analyte were >0.9987. The limits of quantitation ranged from 0.1 to 25 ng/mL. The intra- and inter-day precisions in terms of RSD were
... 30,31) Furthermore, kyn has been reported to be a ligand for AhR. 32,33) Therefore, we next investigated whether AhR and NADPH oxidase are involved in the increase in O 2 ·− production in the presence of vascular endothelium. Pretreatment with the AhR inhibitor CH223191 significantly inhibited kyn-induced O 2 ·− production and partially recovered the decrease in ACh reactivity. ...
The accumulation of uremic toxins is known to be one of the causes of cardiovascular disorder related to renal disease. Among the many uremic toxins, we focused on kynurenine (kyn), whose levels have been shown to be positively correlated with vascular endothelial dysfunction markers, and directly evaluated the influence of kyn on the rat thoracic aorta. Exposure of the endothelium-intact aorta to kyn markedly attenuated the acetylcholine (ACh)-induced relaxation and significantly increased superoxide anion (O2·−) production. These effects were ameliorated by pretreatment with ascorbic acid, an antioxidant, and CH223191, an aryl hydrocarbon receptor (AhR) inhibitor, but not by apocynin, a reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor. In the endothelium-denuded aorta, kyn significantly attenuated the nitric oxide (NO) donor sodium nitroprusside (SNP)-induced vasorelaxation and increased the O2·− production. Ascorbic acid treatment significantly ameliorated these effects, whereas CH223191 and apocynin treatments did not. Kyn had no influence on the vasorelaxant response to BAY 41-2272, a soluble guanylate cyclase stimulator. This suggested that kyn attenuates the NO-mediated vasorelaxation response by promoting O2·− production in thoracic aorta to inactivate NO. O2·− production is likely stimulated in both vascular endothelium and smooth muscle, the former of which may be mediated by AhR activation.
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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. ...
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]. ...
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. ...
Purpose
Induction of IDO depends on the activation of AhR forming the AhR/IDO axis. Activated AhR can transcribe various target genes including cytotoxic and inhibiting receptors of NK cells. We investigated whether AhR and IDO levels as well as activating (NKG2D) and inhibiting (KIR2DL1) NK cell receptors are influenced by acute exercise and different chronic endurance exercise programs.
Methods
21 adult breast and prostate cancer patients of the TOP study (NCT02883699) were randomized to intervention programs of 12 weeks of (1) endurance standard training or (2) endurance polarized training after a cardiopulmonary exercise test (CPET). Serum was collected pre-CPET, immediately post-CPET, 1 h post-CPET and after 12 weeks post-intervention. Flow cytometry analysis was performed on autologous serum incubated NK-92 cells for: AhR, IDO, KIR2DL1 and NKG2D. Differences were investigated using analysis-of-variance for acute and analysis-of-covariance for chronic effects.
Results
Acute exercise: IDO levels changed over time with a significant increase from post-CPET to 1 h post-CPET ( p = 0.03). KIR2DL1 levels significantly decreased over time ( p < 0.01). NKG2D levels remained constant ( p = 0.31). Chronic exercise: for both IDO and NKG2D a significant group × time interaction, a significant time effect and a significant difference after 12 weeks of intervention were observed (IDO: all p < 0.01, NKG2D: all p > 0.05).
Conclusion
Both acute and chronic endurance training may regulate NK cell function via the AhR/IDO axis. This is clinically relevant, as exercise emerges to be a key player in immune regulation.
