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1.
Immunity ; 55(6): 1032-1050.e14, 2022 06 14.
Article in English | MEDLINE | ID: mdl-35704993

ABSTRACT

Conventional dendritic cells (cDCs), cDC1 and cDC2, act both to initiate immunity and maintain self-tolerance. The tryptophan metabolic enzyme indoleamine 2,3-dioxygenase 1 (IDO1) is used by cDCs in maintaining tolerance, but its role in different subsets remains unclear. At homeostasis, only mature CCR7+ cDC1 expressed IDO1 that was dependent on IRF8. Lipopolysaccharide treatment induced maturation and IDO1-dependent tolerogenic activity in isolated immature cDC1, but not isolated cDC2. However, both human and mouse cDC2 could induce IDO1 and acquire tolerogenic function when co-cultured with mature cDC1 through the action of cDC1-derived l-kynurenine. Accordingly, cDC1-specific inactivation of IDO1 in vivo exacerbated disease in experimental autoimmune encephalomyelitis. This study identifies a previously unrecognized metabolic communication in which IDO1-expressing cDC1 cells extend their immunoregulatory capacity to the cDC2 subset through their production of tryptophan metabolite l-kynurenine. This metabolic axis represents a potential therapeutic target in treating autoimmune demyelinating diseases.


Subject(s)
Indoleamine-Pyrrole 2,3,-Dioxygenase , Kynurenine , Animals , Dendritic Cells , Humans , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Kynurenine/metabolism , Mice , Signal Transduction , Tryptophan/metabolism
2.
Immunity ; 46(2): 233-244, 2017 02 21.
Article in English | MEDLINE | ID: mdl-28214225

ABSTRACT

Arginase 1 (Arg1) and indoleamine 2,3-dioxygenase 1 (IDO1) are immunoregulatory enzymes catalyzing the degradation of l-arginine and l-tryptophan, respectively, resulting in local amino acid deprivation. In addition, unlike Arg1, IDO1 is also endowed with non-enzymatic signaling activity in dendritic cells (DCs). Despite considerable knowledge of their individual biology, no integrated functions of Arg1 and IDO1 have been reported yet. We found that IDO1 phosphorylation and consequent activation of IDO1 signaling in DCs was strictly dependent on prior expression of Arg1 and Arg1-dependent production of polyamines. Polyamines, either produced by DCs or released by bystander Arg1+ myeloid-derived suppressor cells, conditioned DCs toward an IDO1-dependent, immunosuppressive phenotype via activation of the Src kinase, which has IDO1-phosphorylating activity. Thus our data indicate that Arg1 and IDO1 are linked by an entwined pathway in immunometabolism and that their joint modulation could represent an important target for effective immunotherapy in several disease settings.


Subject(s)
Arginase/immunology , Dendritic Cells/immunology , Immune Tolerance/physiology , Indoleamine-Pyrrole 2,3,-Dioxygenase/immunology , Signal Transduction/immunology , Animals , Arginase/metabolism , Arginine/immunology , Arginine/metabolism , Blotting, Western , Dendritic Cells/metabolism , Female , Gene Expression Profiling , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Mice , Mice, Inbred C57BL , Real-Time Polymerase Chain Reaction , Transcriptome , Tryptophan/immunology , Tryptophan/metabolism
3.
Hum Mol Genet ; 30(3-4): 265-276, 2021 04 26.
Article in English | MEDLINE | ID: mdl-33693650

ABSTRACT

Mutations in the WFS1 gene, encoding wolframin (WFS1), cause endoplasmic reticulum (ER) stress and are associated with a rare autosomal-recessive disorder known as Wolfram syndrome (WS). WS is clinically characterized by childhood-onset diabetes mellitus, optic atrophy, deafness, diabetes insipidus and neurological signs. We identified two novel WFS1 mutations in a patient with WS, namely, c.316-1G > A (in intron 3) and c.757A > T (in exon 7). Both mutations, located in the N-terminal region of the protein, were predicted to generate a truncated and inactive form of WFS1. We found that although the WFS1 protein was not expressed in peripheral blood mononuclear cells (PBMCs) of the proband, no constitutive ER stress activation could be detected in those cells. In contrast, WS proband's PBMCs produced very high levels of proinflammatory cytokines (i.e. TNF-α, IL-1ß, and IL-6) in the absence of any stimulus. WFS1 silencing in PBMCs from control subjects by means of small RNA interference also induced a pronounced proinflammatory cytokine profile. The same cytokines were also significantly higher in sera from the WS patient as compared to matched healthy controls. Moreover, the chronic inflammatory state was associated with a dominance of proinflammatory T helper 17 (Th17)-type cells over regulatory T (Treg) lymphocytes in the WS PBMCs. The identification of a state of systemic chronic inflammation associated with WFS1 deficiency may pave the way to innovative and personalized therapeutic interventions in WS.


Subject(s)
Inflammation , Leukocytes, Mononuclear/metabolism , Membrane Proteins/genetics , Mutation , Wolfram Syndrome/metabolism , Child , Cytokines/genetics , Cytokines/metabolism , Female , Gene Expression Regulation , Humans , Leukocytes, Mononuclear/immunology , Sequence Analysis, DNA , Wolfram Syndrome/genetics , Wolfram Syndrome/immunology , Wolfram Syndrome/physiopathology
4.
Br J Haematol ; 201(1): 45-57, 2023 04.
Article in English | MEDLINE | ID: mdl-36484163

ABSTRACT

In chronic lymphocytic leukaemia (CLL) the efficacy of SARS-CoV-2 vaccination remains unclear as most studies have focused on humoral responses. Here we comprehensively examined humoral and cellular responses to vaccine in CLL patients. Seroconversion was observed in 55.2% of CLL with lower rate and antibody titres in treated patients. T-cell responses were detected in a significant fraction of patients. CD4+ and CD8+ frequencies were significantly increased independent of serology with higher levels of CD4+ cells in patients under a Bruton tyrosine kinase (BTK) or a B-cell lymphoma 2 (BCL-2) inhibitor. Vaccination skewed CD8+ cells towards a highly cytotoxic phenotype, more pronounced in seroconverted patients. A high proportion of patients showed spike-specific CD4+ and CD8+ cells producing interferon gamma (IFNγ) and tumour necrosis factor alpha (TNFα). Patients under a BTK inhibitor showed increased production of IFNγ and TNFα by CD4+ cells. Vaccination induced a Th1 polarization reverting the Th2 CLL T-cell profile in the majority of patients with lower IL-4 production in untreated and BTK-inhibitor-treated patients. Such robust T-cell responses may have contributed to remarkable protection against hospitalization and death in a cohort of 540 patients. Combining T-cell metrics with seroprevalence may yield a more accurate measure of population immunity in CLL, providing consequential insights for public health.


Subject(s)
Antineoplastic Agents , COVID-19 , Leukemia, Lymphocytic, Chronic, B-Cell , Vaccines , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , COVID-19 Vaccines/therapeutic use , Tumor Necrosis Factor-alpha , SARS-CoV-2 , Seroepidemiologic Studies , COVID-19/prevention & control , Antineoplastic Agents/therapeutic use , Interferon-gamma
5.
Nat Immunol ; 12(9): 870-8, 2011 Jul 31.
Article in English | MEDLINE | ID: mdl-21804557

ABSTRACT

Regulation of tryptophan metabolism by indoleamine 2,3-dioxygenase (IDO) in dendritic cells (DCs) is a highly versatile modulator of immunity. In inflammation, interferon-γ is the main inducer of IDO for the prevention of hyperinflammatory responses, yet IDO is also responsible for self-tolerance effects in the longer term. Here we show that treatment of mouse plasmacytoid DCs (pDCs) with transforming growth factor-ß (TGF-ß) conferred regulatory effects on IDO that were mechanistically separable from its enzymic activity. We found that IDO was involved in intracellular signaling events responsible for the self-amplification and maintenance of a stably regulatory phenotype in pDCs. Thus, IDO has a tonic, nonenzymic function that contributes to TGF-ß-driven tolerance in noninflammatory contexts.


Subject(s)
Adaptive Immunity , Dendritic Cells , Immune Tolerance , Indoleamine-Pyrrole 2,3,-Dioxygenase , Signal Transduction/immunology , Transforming Growth Factor beta/immunology , Adaptive Immunity/drug effects , Animals , Dendritic Cells/cytology , Dendritic Cells/drug effects , Dendritic Cells/enzymology , Dendritic Cells/immunology , Humans , Hypersensitivity/immunology , Immune Tolerance/drug effects , Indoleamine-Pyrrole 2,3,-Dioxygenase/immunology , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Interferon-gamma/immunology , Interferon-gamma/metabolism , Mice , Mice, Inbred BALB C , Mice, Knockout , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Transforming Growth Factor beta/pharmacology , Tryptophan/metabolism
6.
FASEB J ; 36(4): e22218, 2022 04.
Article in English | MEDLINE | ID: mdl-35218567

ABSTRACT

An immunoregulatory role of stem cells, often mediated by their secretome, has been claimed by several studies. Stem cell-derived extracellular vesicles (EVs) are crucial components of the secretome. EVs, a heterogeneous group of membranous vesicles released by many cell types into the extracellular space, are now considered as an additional mechanism for intercellular communication. In this study, we aimed at investigating whether human amniotic stem cell-derived extracellular vesicles (HASC-EVs) were able to interfere with inflammasome activation in the THP-1 cell line. Two subsets of HASC-EVs were collected by sequential centrifugation, namely HASC-P10 and HASC-P100. We demonstrated that HASC-EVs were neither internalized into nor undertake a direct interaction with THP-1 cells. We showed that HASC-P10 and P100 were able to intrinsically produce ATP, which was further converted to adenosine by 5'-nucleotidase (CD73) and ectonucleoside triphosphate diphosphohydrolase-1 (CD39). We found that THP-1 cells conditioned with both types of HASC-EVs failed to activate the NLRP3/caspase-1/inflammasome platform in response to LPS and ATP treatment by a mechanism involving A2a adenosine receptor activation. These results support a role for HASC-EVs as independent metabolic units capable of modifying the cellular functions, leading to anti-inflammatory effects in monocytic cells.


Subject(s)
Amniotic Fluid/cytology , Anti-Inflammatory Agents/pharmacology , Extracellular Vesicles/metabolism , Inflammasomes/antagonists & inhibitors , Inflammation/prevention & control , Monocytes/cytology , Stem Cells/cytology , Adenosine/metabolism , Amniotic Fluid/metabolism , Humans , Inflammation/genetics , Inflammation/metabolism , Inflammation/pathology , Monocytes/metabolism , Purinergic P1 Receptor Antagonists/pharmacology , Receptors, Purinergic P1/chemistry , Receptors, Purinergic P1/metabolism , Stem Cells/metabolism , THP-1 Cells
7.
Proc Natl Acad Sci U S A ; 117(7): 3848-3857, 2020 02 18.
Article in English | MEDLINE | ID: mdl-32024760

ABSTRACT

l-tryptophan (Trp), an essential amino acid for mammals, is the precursor of a wide array of immunomodulatory metabolites produced by the kynurenine and serotonin pathways. The kynurenine pathway is a paramount source of several immunoregulatory metabolites, including l-kynurenine (Kyn), the main product of indoleamine 2,3-dioxygenase 1 (IDO1) that catalyzes the rate-limiting step of the pathway. In the serotonin pathway, the metabolite N-acetylserotonin (NAS) has been shown to possess antioxidant, antiinflammatory, and neuroprotective properties in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). However, little is known about the exact mode of action of the serotonin metabolite and the possible interplay between the 2 Trp metabolic pathways. Prompted by the discovery that NAS neuroprotective effects in EAE are abrogated in mice lacking IDO1 expression, we investigated the NAS mode of action in neuroinflammation. We found that NAS directly binds IDO1 and acts as a positive allosteric modulator (PAM) of the IDO1 enzyme in vitro and in vivo. As a result, increased Kyn will activate the ligand-activated transcription factor aryl hydrocarbon receptor and, consequently, antiinflammatory and immunoregulatory effects. Because NAS also increased IDO1 activity in peripheral blood mononuclear cells of a significant proportion of MS patients, our data may set the basis for the development of IDO1 PAMs as first-in-class drugs in autoimmune/neuroinflammatory diseases.


Subject(s)
Encephalomyelitis, Autoimmune, Experimental/enzymology , Encephalomyelitis, Autoimmune, Experimental/metabolism , Indoleamine-Pyrrole 2,3,-Dioxygenase/chemistry , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Allosteric Regulation , Allosteric Site , Animals , Biocatalysis , Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental/genetics , Female , Humans , Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics , Kynurenine/metabolism , Leukocytes, Mononuclear/metabolism , Male , Mice, Knockout , Multiple Sclerosis/enzymology , Multiple Sclerosis/genetics , Multiple Sclerosis/metabolism , Serotonin/analogs & derivatives , Serotonin/chemistry , Serotonin/metabolism , Tryptophan/metabolism
8.
Int J Mol Sci ; 24(3)2023 Jan 28.
Article in English | MEDLINE | ID: mdl-36768851

ABSTRACT

In pregnancy, human amniotic fluid extracellular vesicles (HAF-EVs) exert anti-inflammatory effects on T cells and on monocytes, supporting their immunoregulatory roles. The specific mechanisms are still not completely defined. The aim of this study was to investigate the ability of HAF-EVs, isolated from pregnant women who underwent amniocentesis and purified by gradient ultracentrifugation, to affect inflammasome activation in the human monocytes. Proteomic studies revealed that HAF-EV samples expressed several immunoregulatory molecules as well as small amounts of endotoxin. Surprisingly, metagenomic analysis shows the presence of specific bacterial strain variants associated with HAF-EVs as potential sources of the endotoxin. Remarkably, we showed that a single treatment of THP-1 cells with HAF-EVs triggered inflammasome activation, whereas the same treatment followed by LPS and ATP sensitization prevented inflammasome activation, a pathway resembling monocyte refractories. A bioinformatics analysis of microbiota-HAF-EVs functional pathways confirmed the presence of enzymes for endotoxin biosynthesis as well as others associated with immunoregulatory functions. Overall, these data suggest that HAF-EVs could serve as a source of the isolation of a specific microbiota during early pregnancy. Moreover, HAF-EVs could act as a novel system to balance immune training and tolerance by modulating the inflammasome in monocytes or other cells.


Subject(s)
Extracellular Vesicles , Microbiota , Humans , Female , Pregnancy , Monocytes/metabolism , Inflammasomes/metabolism , Amniotic Fluid , Proteomics , Extracellular Vesicles/metabolism , Endotoxins/metabolism
9.
Immunity ; 39(2): 372-85, 2013 Aug 22.
Article in English | MEDLINE | ID: mdl-23973224

ABSTRACT

Endogenous tryptophan (Trp) metabolites have an important role in mammalian gut immune homeostasis, yet the potential contribution of Trp metabolites from resident microbiota has never been addressed experimentally. Here, we describe a metabolic pathway whereby Trp metabolites from the microbiota balance mucosal reactivity in mice. Switching from sugar to Trp as an energy source (e.g., under conditions of unrestricted Trp availability), highly adaptive lactobacilli are expanded and produce an aryl hydrocarbon receptor (AhR) ligand-indole-3-aldehyde-that contributes to AhR-dependent Il22 transcription. The resulting IL-22-dependent balanced mucosal response allows for survival of mixed microbial communities yet provides colonization resistance to the fungus Candida albicans and mucosal protection from inflammation. Thus, the microbiota-AhR axis might represent an important strategy pursued by coevolutive commensalism for fine tuning host mucosal reactivity contingent on Trp catabolism.


Subject(s)
Candida albicans/immunology , Interleukins/metabolism , Limosilactobacillus reuteri/metabolism , Receptors, Aryl Hydrocarbon/metabolism , Tryptophan/metabolism , Animals , Basic Helix-Loop-Helix Transcription Factors/deficiency , Basic Helix-Loop-Helix Transcription Factors/genetics , Candidiasis/immunology , Energy Metabolism , Female , Gastrointestinal Tract/immunology , Gastrointestinal Tract/metabolism , Gastrointestinal Tract/microbiology , Indoleamine-Pyrrole 2,3,-Dioxygenase/deficiency , Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics , Indoles/metabolism , Interleukin-17/deficiency , Interleukin-17/genetics , Limosilactobacillus reuteri/growth & development , Limosilactobacillus reuteri/immunology , Metagenome , Mice , Mice, Inbred BALB C , Mice, Inbred C3H , Mice, Inbred C57BL , Mice, Knockout , Mice, SCID , Myeloid Differentiation Factor 88/deficiency , Myeloid Differentiation Factor 88/genetics , Probiotics , Receptors, Aryl Hydrocarbon/deficiency , Receptors, Aryl Hydrocarbon/genetics , Toll-Like Receptor 2/deficiency , Toll-Like Receptor 2/genetics , Tryptophan/chemistry , Interleukin-22
10.
EMBO Rep ; 21(2): e48073, 2020 02 05.
Article in English | MEDLINE | ID: mdl-31867855

ABSTRACT

Apoptotic signalling by p53 occurs at both transcriptional and non-transcriptional levels, as p53 may act as a direct apoptogenic stimulus via activation of the intrinsic mitochondrial pathway. HOPS is a highly conserved, ubiquitously expressed shuttling protein with an ubiquitin-like domain. We generated Hops-/- mice and observed that they are viable with no apparent phenotypic defects. However, when treated with chemotherapeutic agents, Hops-/- mice display a significant reduction in apoptosis, suggesting an impaired ability to respond to genotoxic stressors. We show that HOPS acts as a regulator of cytoplasmic p53 levels and function. By binding p53, HOPS inhibits p53 proteasomal degradation and favours p53 recruitment to mitochondria and apoptosis induction. By interfering with importin α, HOPS further increases p53 cytoplasmic levels. Thus, HOPS promotes the p53-dependent mitochondrial apoptosis pathway by preserving cytoplasmic p53 from both degradation and nuclear uptake.


Subject(s)
Apoptosis , Intracellular Signaling Peptides and Proteins , Membrane Proteins , Mitochondria , Tumor Suppressor Protein p53 , Animals , Apoptosis/genetics , Cytoplasm/genetics , Cytoplasm/metabolism , Mice , Mice, Knockout , Mitochondria/genetics , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism
11.
EMBO Rep ; 21(12): e49756, 2020 12 03.
Article in English | MEDLINE | ID: mdl-33159421

ABSTRACT

Knowledge of a protein's spatial dynamics at the subcellular level is key to understanding its function(s), interactions, and associated intracellular events. Indoleamine 2,3-dioxygenase 1 (IDO1) is a cytosolic enzyme that controls immune responses via tryptophan metabolism, mainly through its enzymic activity. When phosphorylated, however, IDO1 acts as a signaling molecule in plasmacytoid dendritic cells (pDCs), thus activating genomic effects, ultimately leading to long-lasting immunosuppression. Whether the two activities-namely, the catalytic and signaling functions-are spatially segregated has been unclear. We found that, under conditions favoring signaling rather than catabolic events, IDO1 shifts from the cytosol to early endosomes. The event requires interaction with class IA phosphoinositide 3-kinases (PI3Ks), which become activated, resulting in full expression of the immunoregulatory phenotype in vivo in pDCs as resulting from IDO1-dependent signaling events. Thus, IDO1's spatial dynamics meet the needs for short-acting as well as durable mechanisms of immune suppression, both under acute and chronic inflammatory conditions. These data expand the theoretical basis for an IDO1-centered therapy in inflammation and autoimmunity.


Subject(s)
Indoleamine-Pyrrole 2,3,-Dioxygenase , Phosphatidylinositol 3-Kinases , Dendritic Cells/metabolism , Humans , Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Inflammation , Phosphatidylinositol 3-Kinases/genetics , Signal Transduction
12.
J Biol Chem ; 295(33): 11866-11876, 2020 08 14.
Article in English | MEDLINE | ID: mdl-32616652

ABSTRACT

Garcinoic acid (GA or δ-T3-13'COOH), is a natural vitamin E metabolite that has preliminarily been identified as a modulator of nuclear receptors involved in ß-amyloid (Aß) metabolism and progression of Alzheimer's disease (AD). In this study, we investigated GA's effects on Aß oligomer formation and deposition. Specifically, we compared them with those of other vitamin E analogs and the soy isoflavone genistein, a natural agonist of peroxisome proliferator-activated receptor γ (PPARγ) that has therapeutic potential for managing AD. GA significantly reduced Aß aggregation and accumulation in mouse cortical astrocytes. Similarly to genistein, GA up-regulated PPARγ expression and apolipoprotein E (ApoE) efflux in these cells with an efficacy that was comparable with that of its metabolic precursor δ-tocotrienol and higher than those of α-tocopherol metabolites. Unlike for genistein and the other vitamin E compounds, the GA-induced restoration of ApoE efflux was not affected by pharmacological inhibition of PPARγ activity, and specific activation of pregnane X receptor (PXR) was observed together with ApoE and multidrug resistance protein 1 (MDR1) membrane transporter up-regulation in both the mouse astrocytes and brain tissue. These effects of GA were associated with reduced Aß deposition in the brain of TgCRND8 mice, a transgenic AD model. In conclusion, GA holds potential for preventing Aß oligomerization and deposition in the brain. The mechanistic aspects of GA's properties appear to be distinct from those of other vitamin E metabolites and of genistein.


Subject(s)
Amyloid beta-Peptides/metabolism , Benzopyrans/pharmacology , Brain/drug effects , Protein Aggregation, Pathological/prevention & control , Vitamin E/analogs & derivatives , Amyloid beta-Peptides/ultrastructure , Animals , Benzopyrans/pharmacokinetics , Brain/metabolism , Brain/pathology , Male , Mice , Protein Aggregates/drug effects , Protein Aggregation, Pathological/pathology , Vitamin E/pharmacokinetics , Vitamin E/pharmacology
13.
Int J Mol Sci ; 22(9)2021 Apr 28.
Article in English | MEDLINE | ID: mdl-33924971

ABSTRACT

The Aryl hydrocarbon receptor (AhR) is a critical regulator of both innate and adaptive immune responses, with potent immunomodulatory effects that makes this receptor an attractive molecular target for novel therapeutics. Accumulating evidence indicates that diverse-both host's and microbial-tryptophan metabolites profoundly regulate the immune system in the host via AhR, promoting either tolerance or immunity, largely as a function of the qualitative and quantitative nature of the metabolites being contributed by either source. Additional findings indicate that host and microbiota-derived tryptophan metabolic pathways can influence the outcome of immune responses to tumors. Here, we review recent studies on the role and modalities of AhR activation by various ligands, derived from either host-cell or microbial-cell tryptophan metabolic pathways, in the regulation of immune responses. Moreover, we highlight potential implications of those ligands and pathways in tumor immunotherapy, with particular relevance to checkpoint-blockade immune intervention strategies.


Subject(s)
Receptors, Aryl Hydrocarbon/metabolism , Tryptophan/metabolism , Animals , Humans , Immunotherapy , Ligands , Neoplasms/therapy
14.
Int J Mol Sci ; 22(2)2021 Jan 13.
Article in English | MEDLINE | ID: mdl-33451129

ABSTRACT

The aryl-hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates numerous cellular responses. Originally investigated in toxicology because of its ability to bind environmental contaminants, AhR has attracted enormous attention in the field of immunology in the last 20 years. In addition, the discovery of endogenous and plant-derived ligands points to AhR also having a crucial role in normal cell physiology. Thus, AhR is emerging as a promiscuous receptor that can mediate either toxic or physiologic effects upon sensing multiple exogenous and endogenous molecules. Within this scenario, several factors appear to contribute to the outcome of gene transcriptional regulation by AhR, including the nature of the ligand as such and its further metabolism by AhR-induced enzymes, the local tissue microenvironment, and the presence of coregulators or specific transcription factors in the cell. Here, we review the current knowledge on the array of transcription factors and coregulators that, by interacting with AhR, tune its transcriptional activity in response to endogenous and exogenous ligands.


Subject(s)
Basic Helix-Loop-Helix Transcription Factors/metabolism , Drug Discovery , Ligands , Receptors, Aryl Hydrocarbon/metabolism , Animals , Basic Helix-Loop-Helix Transcription Factors/genetics , Carrier Proteins , Drug Discovery/methods , Gene Expression Regulation/drug effects , Humans , Immunomodulation , Protein Binding , Receptors, Aryl Hydrocarbon/genetics , Transcription Factors/metabolism
15.
Rev Med Virol ; 29(4): e2048, 2019 07.
Article in English | MEDLINE | ID: mdl-31265195

ABSTRACT

Seropositivity for HSV reaches more than 70% within the world population, and yet no approved vaccine exists. While HSV1 is responsible for keratitis, encephalitis, and labialis, HSV2 carriers have a high susceptibility to other STD infections, such as HIV. Induction of antiviral innate immune responses upon infection depends on a family of pattern recognition receptors called Toll-like receptors (TLR). TLRs bridge innate and adaptive immunity by sensing virus infection and activating antiviral immune responses. HSV adopts smart tricks to evade innate immunity and can also manipulate TLR signaling to evade the immune system or even confer destructive effects in favor of virus replication. Here, we review mechanisms by which HSV can trick TLR signaling to impair innate immunity. Then, we analyze the role of HSV-mediated molecular cues, in particular, NF-κB signaling, in promoting protective versus destructive effects of TLRs. Finally, TLR-based therapeutic opportunities with the goal of preventing or treating HSV infection will be discussed.


Subject(s)
Biological Therapy/methods , Herpes Simplex/immunology , Herpes Simplex/therapy , Immunity, Innate , Simplexvirus/immunology , Toll-Like Receptors/metabolism , Host Microbial Interactions , Humans , Immune Evasion , Simplexvirus/pathogenicity
16.
Nature ; 511(7508): 184-90, 2014 Jul 10.
Article in English | MEDLINE | ID: mdl-24930766

ABSTRACT

Disease tolerance is the ability of the host to reduce the effect of infection on host fitness. Analysis of disease tolerance pathways could provide new approaches for treating infections and other inflammatory diseases. Typically, an initial exposure to bacterial lipopolysaccharide (LPS) induces a state of refractoriness to further LPS challenge (endotoxin tolerance). We found that a first exposure of mice to LPS activated the ligand-operated transcription factor aryl hydrocarbon receptor (AhR) and the hepatic enzyme tryptophan 2,3-dioxygenase, which provided an activating ligand to the former, to downregulate early inflammatory gene expression. However, on LPS rechallenge, AhR engaged in long-term regulation of systemic inflammation only in the presence of indoleamine 2,3-dioxygenase 1 (IDO1). AhR-complex-associated Src kinase activity promoted IDO1 phosphorylation and signalling ability. The resulting endotoxin-tolerant state was found to protect mice against immunopathology in Gram-negative and Gram-positive infections, pointing to a role for AhR in contributing to host fitness.


Subject(s)
Disease Resistance/genetics , Disease Resistance/immunology , Receptors, Aryl Hydrocarbon/metabolism , Animals , Bacterial Infections/immunology , Bacterial Infections/metabolism , Disease Resistance/drug effects , Endotoxemia/genetics , Endotoxemia/immunology , Endotoxemia/metabolism , Enzyme Activation/drug effects , Gene Expression Regulation/drug effects , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Inflammation/enzymology , Inflammation/genetics , Inflammation/metabolism , Kynurenine/metabolism , Lipopolysaccharides/pharmacology , Mice , Phosphorylation , Receptors, Aryl Hydrocarbon/genetics , Signal Transduction , Tryptophan Oxygenase/metabolism , src-Family Kinases/metabolism
17.
J Cell Mol Med ; 23(5): 3757-3761, 2019 05.
Article in English | MEDLINE | ID: mdl-30793469

ABSTRACT

The cytokine interleukin IL-35 is known to exert strong immunosuppressive functions. Indoleamine 2,3-dioxygenase 1 (IDO1) and Arginase 1 (Arg1) are metabolic enzymes that, expressed by dendritic cells (DCs), contribute to immunoregulation. Here, we explored any possible link between IL-35 and the activity of those enzymes. We transfected a single chain IL-35Ig gene construct in murine splenic DCs (DC35 ) and assessed any IDO1 and Arg1 activities as resulting from ectopic IL-35Ig expression, both in vitro and in vivo. Unlike Ido1, Arg1 expression was induced in vitro in DC35 , and it conferred an immunosuppressive phenotype on those cells, as revealed by a delayed-type hypersensitivity assay. Moreover, the in vivo onset of a tolerogenic phenotype in DC35 was associated with the detection of CD25+ CD39+ , rather than Foxp3+ , regulatory T cells. Therefore, Arg1, but not Ido1, expression in DC35 appears to be an early event in IL-35Ig-mediated immunosuppression.


Subject(s)
Arginase/immunology , Dendritic Cells/immunology , Immune Tolerance/immunology , Interleukins/immunology , Animals , Antigens, CD/immunology , Antigens, CD/metabolism , Apyrase/immunology , Apyrase/metabolism , Arginase/genetics , Arginase/metabolism , Dendritic Cells/metabolism , Female , Forkhead Transcription Factors/immunology , Forkhead Transcription Factors/metabolism , Immune Tolerance/genetics , Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics , Indoleamine-Pyrrole 2,3,-Dioxygenase/immunology , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Interleukin-2 Receptor alpha Subunit/immunology , Interleukin-2 Receptor alpha Subunit/metabolism , Interleukin-4/genetics , Interleukin-4/immunology , Interleukin-4/metabolism , Interleukins/genetics , Interleukins/metabolism , Mice, Inbred C57BL , Mice, Knockout , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Transforming Growth Factor beta/genetics , Transforming Growth Factor beta/immunology , Transforming Growth Factor beta/metabolism
18.
J Biol Chem ; 292(5): 1785-1797, 2017 02 03.
Article in English | MEDLINE | ID: mdl-27994058

ABSTRACT

Indoleamine 2,3-dioxygenase 1 (IDO1) is a single chain oxidoreductase that catalyzes tryptophan degradation to kynurenine. In cancer, it exerts an immunosuppressive function as part of an acquired mechanism of immune escape. Recently, we demonstrated that IDO1 expression is significantly higher in all thyroid cancer histotypes compared with normal thyroid and that its expression levels correlate with T regulatory (Treg) lymphocyte densities in the tumor microenvironment. BRAFV600E- and RET/PTC3-expressing PcCL3 cells were used as cellular models for the evaluation of IDO1 expression in thyroid carcinoma cells and for the study of involved signal transduction pathways. BRAFV600E-expressing PcCL3 cells did not show IDO1 expression. Conversely, RET/PTC3-expressing cells were characterized by a high IDO1 expression. Moreover, we found that, the STAT1-IRF1 pathway was instrumental for IDO1 expression in RET/PTC3 expressing cells. In detail, RET/PTC3 induced STAT1 overexpression and phosphorylation at Ser-727 and Tyr-701. STAT1 transcriptional regulation appeared to require activation of the canonical NF-κB pathway. Conversely, activation of the MAPK and PI3K-AKT pathways primarily regulated Ser-727 phosphorylation, whereas a physical interaction between RET/PTC3 and STAT1, followed by a direct tyrosine phosphorylation event, was necessary for STAT1 Tyr-701 phosphorylation. These data provide the first evidence of a direct link between IDO1 expression and the oncogenic activation of RET in thyroid carcinoma and describe the involved signal transduction pathways. Moreover, they suggest possible novel molecular targets for the abrogation of tumor microenvironment immunosuppression. The detection of those targets is becoming increasingly important to yield the full function of novel immune checkpoint inhibitors.


Subject(s)
Gene Expression Regulation, Enzymologic , Indoleamine-Pyrrole 2,3,-Dioxygenase/biosynthesis , MAP Kinase Signaling System , Proto-Oncogene Proteins c-ret/metabolism , STAT1 Transcription Factor/metabolism , Thyroid Neoplasms/metabolism , Amino Acid Substitution , Animals , Cell Line , Cell Line, Tumor , Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics , Mutation, Missense , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins B-raf/metabolism , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-ret/genetics , Rats , STAT1 Transcription Factor/genetics , Thyroid Neoplasms/genetics , Thyroid Neoplasms/pathology , Tumor Microenvironment/genetics
19.
Int J Cancer ; 143(9): 2105-2115, 2018 11 01.
Article in English | MEDLINE | ID: mdl-29574719

ABSTRACT

Cytokine members of the IL-12 family have attracted enormous attention in the last few years, with IL-35 being the one of the most attractive-suppressive cytokine. IL-35 is an important mediator of regulatory T cell function. Regulatory T cells play key roles in restoring immune homeostasis after facing challenges such as infection by specific pathogens. Moreover, a crucial role for regulatory T cell populations has been demonstrated in several physiological processes, including establishment of fetal-maternal tolerance, maintenance of self-tolerance and prevention of autoimmune diseases. However, a deleterious involvement of immune regulatory T cells has been documented in specific inhibition of immune responses against tumor cells, promotion of chronic infections and establishment of chronic inflammatory disorders. In this review, we attempt to shed light on the concept of immune-homoeostasis on the aforementioned issues, taking IL-35 as the hallmark of regulatory responses. The dilemma between immune-mediated cancer treatment and inflammation is discussed. Histopathological indications of chronic vs. acute infections are elaborated. Moreover, the evidence that IL-35 requires additional immune-regulatory cytokines, such as IL-10 and TGF-ß, to induce effective and maximal anti-inflammatory effects suggest that immune-regulation requires multi-factorial analysis of many immune playmakers rather than a specific immune target.


Subject(s)
Chronic Disease , Immune Tolerance/immunology , Infections/immunology , Inflammation/immunology , Interleukins/immunology , Neoplasms/immunology , T-Lymphocytes, Regulatory/immunology , Disease Progression , Humans
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