Sensing of an HIV-1-Derived Single-Stranded RNA-Oligonucleotide Induces Arginase 1-Mediated Tolerance.

Small synthetic oligodeoxynucleotides (ODNs) can mimic microbial nucleic acids by interacting with receptor systems and promoting immunostimulatory activities. Nevertheless, some ODNs can act differently on the plasmacytoid dendritic cell (pDC) subset, shaping their immunoregulatory properties and rendering them suitable immunotherapeutic tools in several clinical settings for treating overwhelming immune responses. We designed HIV-1-derived, DNA- and RNA-based oligonucleotides (gag, pol, and U5 regions) and assessed their activity in conferring a tolerogenic phenotype to pDCs in skin test experiments.

Epacadostat stabilizes the apo-form of IDO1 and signals a pro-tumorigenic pathway in human ovarian cancer cells.

The tryptophan-degrading enzyme indoleamine 2,3-dioxygenase 1 (IDO1) is a plastic immune checkpoint molecule that potently orchestrates immune responses within the tumor microenvironment (TME). As a heme-containing protein, IDO1 catalyzes the conversion of the essential amino acid tryptophan into immunoactive metabolites, called kynurenines. By depleting tryptophan and enriching the TME with kynurenines, IDO1 catalytic activity shapes an immunosuppressive TME.

Membrane Localization and Phosphorylation of Indoleamine 2,3-Dioxygenase 2 (IDO2) in A549 Human Lung Adenocarcinoma Cells: First Steps in Exploring Its Signaling Function.

Indoleamine 2,3-dioxygenase 2 (IDO2) is a paralog of Indoleamine 2,3-dioxygenase 1 (IDO1), a tryptophan-degrading enzyme producing immunomodulatory molecules. However, the two proteins are unlikely to carry out the same functions. IDO2 shows little or no tryptophan catabolic activity and exerts contrasting immunomodulatory roles in a context-dependent manner in cancer and autoimmune diseases.

The catalytic inhibitor epacadostat can affect the non-enzymatic function of IDO1.

Indoleamine 2,3-dioxygenase 1 (IDO1) is a tryptophan metabolizing enzyme chronically activated in many cancer patients and its expression and activity correlate with a poor prognosis. In fact, it acts as an immune regulator and contributes to tumor-induced immunosuppression by determining tryptophan deprivation and producing immunosuppressive metabolites named kynurenines. These findings made IDO1 an attractive target for cancer immunotherapy and small-molecule inhibitors, such as epacadostat, have been developed to block its enzymatic activity.

The circadian control of tryptophan metabolism regulates the host response to pulmonary fungal infections.

The environmental light/dark cycle has left its mark on the body's physiological functions to condition not only our inner biology, but also the interaction with external cues. In this scenario, the circadian regulation of the immune response has emerged as a critical factor in defining the host-pathogen interaction and the identification of the underlying circuitry represents a prerequisite for the development of circadian-based therapeutic strategies. The possibility to track down the circadian regulation of the immune response to a metabolic pathway would represent a unique opportunity in this direction.

Modulation of Indoleamine 2,3-Dioxygenase 1 During Inflammatory Bowel Disease Activity in Humans and Mice.

Background And Aims: Indoleamine 2,3 dioxygenase-1 (IDO1), a key enzyme in tryptophan metabolism, is strongly up-regulated both in human inflammatory bowel disease (IBD) and animal models of colitis, however its role in the pathogenesis is still controversial. In this study, we investigated IDO1 expression and activity in a mouse model of DSS-induced chronic colitis as well as in colon biopsies and sera from IBD patients.

Methods: Chronic colitis was induced in mice through the oral administration of dextran sodium sulfate (DSS), and IDO1 activity was induced by i.

The signaling function of IDO1 incites the malignant progression of mouse B16 melanoma.

Indoleamine 2,3 dioxygenase 1 (IDO1), a leader tryptophan-degrading enzyme, represents a recognized immune checkpoint molecule. In neoplasia, IDO1 is often highly expressed in dendritic cells infiltrating the tumor and/or in tumor cells themselves, particularly in human melanoma. In dendritic cells, IDO1 does not merely metabolize tryptophan into kynurenine but, after phosphorylation of critical tyrosine residues in the non-catalytic small domain, it triggers a signaling pathway prolonging its immunoregulatory effects by a feed-forward mechanism.

DNA Methylation Levels and Serum Kynurenine/Tryptophan Ratio in Eating Disorders: A Possible Link with Psychopathological Traits?

Background: The incidence of eating disorders (EDs), serious mental and physical conditions characterized by a disturbance in eating or eating-related behaviors, has increased steadily. The present study aims to develop insights into the pathophysiology of EDs, spanning over biochemical, epigenetic, psychopathological, and clinical data. In particular, we focused our attention on the relationship between (i) DNA methylation profiles at promoter-associated CpG sites of the SCL6A4 gene, (ii) serum kynurenine/tryptophan levels and ratio (Kyn/Trp), and (iii) psychopathological traits in a cohort of ED patients.

The immunosuppression pathway of tumor-associated macrophages is controlled by heme oxygenase-1 in glioblastoma patients.

The immunosuppressive tumor microenvironment (TME) in glioblastoma (GBM) is mainly driven by tumor-associated macrophages (TAMs). We explored whether their sustained iron metabolism and immunosuppressive activity were correlated, and whether blocking the central enzyme of the heme catabolism pathway, heme oxygenase-1 (HO-1), could reverse their tolerogenic activity. To this end, we investigated iron metabolism in bone marrow-derived macrophages (BMDMs) isolated from GBM specimens and in in vitro-derived macrophages (Mφ) from healthy donor (HD) blood monocytes.

L. Petal Extract Inhibits Inflammation and Osteoclastogenesis in RAW 264.7 Cell Model.

The dried stigmas of L. (Iridaceae) are traditionally processed to produce saffron, a spice widely used as a food coloring and flavoring agent, which is important in the pharmaceutical and textile dye-producing industries. The labor-intensive by-hand harvesting and the use of only a small amount of each flower cause saffron to be the most expensive spice in the world.

Indoleamine 2,3-dioxygenase 1 activation in mature cDC1 promotes tolerogenic education of inflammatory cDC2 via metabolic communication.

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.

Decoding the Complex Crossroad of Tryptophan Metabolic Pathways.

Among the 20 amino acids needed for protein synthesis, Tryptophan (Trp) is an aromatic amino acid fundamental not only for the synthesis of the major components of living cells (namely, the proteins), but also for the maintenance of cellular homeostasis [...

Emulgel Loaded with Flaxseed Extracts as New Therapeutic Approach in Wound Treatment.

Dry (D.E.) and liquid (L.

Pathogenetic Interplay Between IL-6 and Tryptophan Metabolism in an Experimental Model of Obesity.

Obesity is a metabolic disease characterized by a state of chronic, low-grade inflammation and dominated by pro-inflammatory cytokines such as IL-6. Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme that catalyzes the first step in the kynurenine pathway by transforming l-tryptophan (Trp) into l-kynurenine (Kyn), a metabolite endowed with anti-inflammatory and immunoregulatory effects. In dendritic cells, IL-6 induces IDO1 proteasomal degradation and shuts down IDO1-mediated immunosuppressive effects.

Indoleamine 2,3-dioxygenase 1 (IDO1): an up-to-date overview of an eclectic immunoregulatory enzyme.

Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the initial rate-limiting step in the degradation of the essential amino acid tryptophan along the kynurenine pathway. When discovered more than 50 years ago, IDO1 was thought to be an effector molecule capable of mediating a survival strategy based on the deprivation of bacteria and tumor cells of the essential amino acid tryptophan. Since 1998, when tryptophan catabolism was discovered to be crucially involved in the maintenance of maternal T-cell tolerance, IDO1 has become the focus of several laboratories around the world.

Novel mutations in the WFS1 gene are associated with Wolfram syndrome and systemic inflammation.

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.

Extract Inhibits LPS-Triggered Inflammation Markers and Suppresses RANKL-Induced Osteoclastogenesis in RAW264.7.

() leaf decoction, a traditional remedy prepared in North by the Hmong ethnic group, is a tea extract rich in bioactive compounds that may have therapeutic effects in arthritis and backache. Indeed, it has been demonstrated that is able to inhibit Th17 lymphocytes development and to protect mice in an experimental model of collagen-induced arthritis. By resorting to macrophage models of inflammation and osteoclastogenesis, we showed that extract significantly reduced nitric oxide synthase 2 (NOS2) activity and IL-6 production by RAW 264.

Class IA PI3Ks regulate subcellular and functional dynamics of IDO1.

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.

Effect of Probiotic Administration on Serum Tryptophan Metabolites in Pediatric Type 1 Diabetes Patients.

Type 1 diabetes (T1D) is characterized by anomalous functioning of the immuno regulatory, tryptophan-catabolic enzyme indoleamine 2,3 dioxygenase 1 (IDO1). In T1D, the levels of kynurenine-the first byproduct of tryptophan degradation via IDO1-are significantly lower than in nondiabetic controls, such that defective immune regulation by IDO1 has been recognized as potentially contributing to autoimmunity in T1D. Because tryptophan catabolism-and the production of immune regulatory catabolites-also occurs via the gut microbiota, we measured serum levels of tryptophan, and metabolites thereof, in pediatric, diabetic patients after a 3-month oral course of GG.

Potential Benefits of Tryptophan Metabolism to the Efficacy of Tocilizumab in COVID-19.

Tocilizumab has been proposed as a means of opposing hyperinflammatory responses in intensive care patients with COVID-19. Here, we briefly discuss the potentially multiple, synergistic mechanisms whereby tocilizumab might exert therapeutic activity, mostly focusing on the production of tryptophan-derived catabolites that would result from blockade of IL-6 signaling, as contextualized to the cytokine storm occurring in COVID-19 patients.

A novel mutation of indoleamine 2,3-dioxygenase 1 causes a rapid proteasomal degradation and compromises protein function.

Indoleamine 2,3-dioxygenase 1 (IDO1) - the enzyme catalyzing the rate-limiting step of tryptophan catabolism along the kynurenine pathway - belongs to the class of inhibitory immune checkpoint molecules. Such regulators of the immune system are crucial for maintaining self-tolerance and thus, when properly working, preventing autoimmunity. A dysfunctional IDO1 has recently been associated with a specific single nucleotide polymorphism (SNP) and with the occurrence of autoimmune diabetes and multiple sclerosis.