Human myeloid dendritic cells are refractory to tryptophan metabolites

Bubnoff, Dagmar von; Wilms, Helene; Scheler, Marina; Brenk, Manuela; Koch, Susanne; Bieber, Thomas

doi:10.1016/j.humimm.2011.05.026

Cited by 4 publications

(4 citation statements)

References 36 publications

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“…Trp metabolites do not induce cell death in human myeloid DCs, contrary to what has been reported for mouse and human T cells (29). Furthermore, increased trp catabolite concentrations in either low-or normal-trp conditions do not alter the stimulatory function of human myeloid DCs in vitro (34). In contrast, in mice, it has been shown that IDO pathway metabolites can initiate tolerogenesis in immunogenic DCs in the absence of IDO by the uptake of these catabolites in an IFN-c-rich environment (35).…”

Section: Immune Tolerance Induction Through Trp Starvation and Trp Mecontrasting

confidence: 64%

The indoleamine 2,3‐dioxygenase (IDO) pathway controls allergy

Bubnoff

Bieber

2012

Allergy

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A series of recent studies have demonstrated that the immunoregulatory pathway of tryptophan catabolism, initiated by the enzyme indoleamine 2,3-dioxygenase (IDO), is a critical participant in allergic inflammation. Originally known for its regulatory function during pregnancy and during chronic inflammation in tumorigenesis and infection, the activity of IDO seems to positively modify the inflammatory state of atopy or allergy. The tryptophan degradation pathway is important for tolerance induction during systemic allergen immunotherapy. Here, we focus on recent findings that establish the IDO pathway as central to allergic inflammation.The indoleamine 2,3-dioxygenase (IDO) pathway has been found to contribute substantially to the control of allergic inflammation. Traditionally recognized for its immunomodulatory role in infection, pregnancy, autoimmunity, and neoplasia, the effect of IDO on allergy appears to be a another piece of puzzle in the 'hygiene hypothesis'. Early microbial exposure and thus the stimulation of the IDO pathway by distinct Toll-like receptors (TLR) may, together with other immunoregulatory pathways, shape the predisposition to and determine the outcome of allergic inflammation, autoimmunity, and probably other diseases. Current data suggest that a normal induction of IDO activity, which decreases serum tryptophan (trp) levels and increases the levels of trp metabolites, controls the allergic inflammation. The mechanism of IDO-induced tolerance induction can probably be manifold but the induction of regulatory T cells may be a major aspect of the control function over allergic inflammation. This review summarizes the current knowledge on the IDO pathway and its role in regulating immune functions with a focus on allergic diseases.Tryptophan and its degradation pathways: indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase (TDO)As an essential amino acid, tryptophan (trp) is a constituent of proteins. Inadequate dietary intake of trp and other essential amino acids can lead to a negative nitrogen balance and to a loss of muscle mass, brain size, and weight (1). Trp is an essential starting point of two biochemical pathways: (i) the enzyme tryptophan 5-hydroxylase converts trp into 5-hydroxytryptophan, which is subsequently decarboxylized to 5-hydroxytryptamine (5-HT, serotonin), an essential neurotransmitter and vasoconstrictor, and (ii) two atoms of the molecular oxygen are inserted into L-trp to form N-formylkynurenine, the first and rate-limiting step in the kynurenine pathway (Fig. 1) (2, 3). The activation of molecular oxygen and its insertion into trp are catalyzed by three

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Section: Immune Tolerance Induction Through Trp Starvation and Trp Mecontrasting

confidence: 64%

The indoleamine 2,3‐dioxygenase (IDO) pathway controls allergy

Bubnoff

Bieber

2012

Allergy

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“…However, the effect of Trp degradation on human DCs is still unclear. For instance, it has been demonstrated in vitro that human DCs increased the expression of inhibitory receptors and showed significantly lower stimulatory capacity toward T cells under low Trp concentration conditions, but no difference on the stimulatory capacity was observed when a mixture of the metabolites anthranilic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic acid, and quinolinic acid was added a prior to the medium; contrarily of what was ob-served for T-cells [50]. On the other hand, Belladonna et al showed that nearby produced kynurenines and derived metabolites can be taken up by murine DCs inducing a tolerogenic phenotype, independently of Trp availability and IDO activity, i.e., IDO-competent cells can "transfer" tolerogenic potential to DCs lacking functional IDO by producing Trp metabolites [51].…”

Section: Immunomodulatory Supernatants and Bioactive Pathwaysmentioning

confidence: 99%

Mining for Active Molecules in Probiotic Supernatant by Combining Non-Targeted Metabolomics and Immunoregulation Testing

et al. 2022

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Chronic respiratory diseases such as asthma are highly prevalent in industrialized countries. As cases are expected to rise, there is a growing demand for alternative therapies. Our recent research on the potential benefits of probiotics suggests that they could prevent and reduce the symptoms of many diseases by modulating the host immune system with secreted metabolites. This article presents the first steps of the research that led us to identify the immunoregulatory bioactivity of the amino acid d-Trp reported in our previous study. Here we analyzed the cell culture metabolic footprinting of 25 commercially available probiotic strains to associate metabolic pathway activity information with their respective immune modulatory activity observed in vitro. Crude probiotic supernatant samples were processed in three different ways prior to untargeted analysis in positive and negative ionization mode by direct infusion ESI-FT-ICR-MS: protein precipitation and solid phase extraction (SPE) using HLB and CN-E sorbent cartridges. The data obtained were submitted to multivariate statistical analyses to distinguish supernatant samples into the bioactive and non-bioactive group. Pathway analysis using discriminant molecular features showed an overrepresentation of the tryptophan metabolic pathway for the bioactive supernatant class, suggesting that molecules taking part in that pathway may be involved in the immunomodulatory activity observed in vitro. This work showcases the potential of metabolomics to drive product development and novel bioactive compound discovery out of complex biological samples in a top-down manner.

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“…[70][71][72][73] In addition, IL-6, IL-10, IFNa, IFNb, vitamin D3, low tryptophan and aspirin also induce DC tolerance through upregulation of LILRB4. [74][75][76][77][78][79] The fine balance of DC regulation between tolerogenic and inflammatory states may contribute to the development of autoimmune diseases, tolerance of transplanting, and tumor immune evasion. Treatment with recombinant human LILRB4-ECD-Fc proteins or upregulation of mouse endogenous gp49B induces DC tolerance to inhibit a variety of autoimmune diseases, such as systemic lupus erythematosus, collagen-induced arthritis, autoimmune encephalomyelitis and inflammatory bowel disease; in contrast, blocking LILRB4 or gp49b deficiency exacerbates autoimmune diseases.…”

Section: Dendritic Cellsmentioning

confidence: 99%

“…The tolerogenic crosstalk between Treg/Ts cells and tDCs is partly carried out by the inhibitory receptor LILRB4 70–73 . In addition, IL-6, IL-10, IFNα, IFNβ, vitamin D3, low tryptophan and aspirin also induce DC tolerance through upregulation of LILRB4 74–79 . The fine balance of DC regulation between tolerogenic and inflammatory states may contribute to the development of autoimmune diseases, tolerance of transplanting, and tumor immune evasion.…”

Section: Introductionmentioning

confidence: 99%

LILRB4, an immune checkpoint on myeloid cells

et al. 2022

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Leukocyte immunoglobulin-like receptor B4 (LILRB4) is an inhibitory receptor in the LILR family mainly expressed on normal and malignant human cells of myeloid origin. By binding to ligands, LILRB4 is activated and subsequently recruits adaptors to cytoplasmic immunoreceptor tyrosine inhibitory motifs to initiate different signaling cascades, thus playing an important role in physiological and pathological conditions, including autoimmune diseases, microbial infections, and cancers. In normal myeloid cells, LILRB4 regulates intrinsic cell activation and differentiation. In disease-associated or malignant myeloid cells, LILRB4 is significantly correlated with disease severity or patient survival and suppresses T cells, thereby participating in the pathogenesis of various diseases. In summary, LILRB4 functions as an immune checkpoint on myeloid cells and may be a promising therapeutic target for various human immune diseases, especially for cancer immunotherapy.

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Human myeloid dendritic cells are refractory to tryptophan metabolites

Cited by 4 publications

References 36 publications

The indoleamine 2,3‐dioxygenase (IDO) pathway controls allergy

The indoleamine 2,3‐dioxygenase (IDO) pathway controls allergy

Mining for Active Molecules in Probiotic Supernatant by Combining Non-Targeted Metabolomics and Immunoregulation Testing

LILRB4, an immune checkpoint on myeloid cells

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