Metabolic adaptation of myeloid cells in the glioblastoma microenvironment.

In recent decades, immunometabolism in cancers has emerged as an interesting target for treatment development. Indeed, the tumor microenvironment (TME) unique characteristics such as hypoxia and limitation of nutrients availability lead to a switch in metabolic pathways in both tumor and TME cells in order to support their adaptation and grow. Glioblastoma (GBM), the most frequent and aggressive primary brain tumor in adults, has been extensively studied in multiple aspects regarding its immune population, but research focused on immunometabolism remains limited.

Parallel single-cell metabolic analysis and extracellular vesicle profiling reveal vulnerabilities with prognostic significance in acute myeloid leukemia.

Acute myeloid leukemia (AML) is an aggressive disease with a high relapse rate. In this study, we map the metabolic profile of CD34(CD38) AML cells and the extracellular vesicle signatures in circulation from AML patients at diagnosis. CD34 AML cells display high antioxidant glutathione levels and enhanced mitochondrial functionality, both associated with poor clinical outcomes.

A Deeply Quiescent Subset of CML LSC depend on FAO yet Avoid Deleterious ROS by Suppressing Mitochondrial Complex I.

Background And Objective: Disease relapse and therapy resistance remain serious impediments to treating cancer. Leukemia stem cells (LSC) are therapy resistant and the cause of relapse. A state of deep quiescence appears to enable cancer stem cells (CSC) to acquire new somatic mutations essential for disease progression and therapy resistance.

Measuring the Metabolic State of Tissue-Resident Macrophages via SCENITH.

Functional reprograming of cells is linked to a process of metabolic rewiring that is adapted for such new functions or microenvironment. Macrophages are present in all tissues and exposed to different microenvironments throughout our body. Profiling energetic metabolism of tissue resident and other heterogeneous populations of macrophages in vitro and ex vivo is technologically very challenging.

Human cDC1s display constitutive activation of the UPR sensor IRE1.

The intracellular mechanisms safeguarding DC function are of biomedical interest in several immune-related diseases. Type 1 conventional DCs (cDC1s) are prominent targets of immunotherapy typified by constitutive activation of the unfolded protein response (UPR) sensor IRE1. Through its RNase domain, IRE1 regulates key processes in cDC1s including survival, ER architecture and function.

Dysregulated Immune Responses in COVID-19 Patients Correlating With Disease Severity and Invasive Oxygen Requirements.

The prognosis of severe COVID-19 patients has motivated research communities to uncover mechanisms of SARS-CoV-2 pathogenesis also on a regional level. In this work, we aimed to understand the immunological dynamics of severe COVID-19 patients with different degrees of illness, and upon long-term recovery. We analyzed immune cellular subsets and SARS-CoV-2-specific antibody isotypes of 66 COVID-19 patients admitted to the Hospital Clínico Universidad de Chile, which were categorized according to the WHO ten-point clinical progression score.

Heat-killed Helicobacter pylori upregulates NKG2D ligands expression on gastric adenocarcinoma cells via Toll-like receptor 4.

Background: Natural killer (NK) cells are paramount for immunity against infectious agents and tumors. Their cytokine and cytolytic responses can be mediated by natural killer group 2, member D (NKG2D), an activating receptor whose ligands (NKG2DL) expression is induced in conditions of cell stress and malignant transformation. Since sustained expression of NKG2DL MICA is related to lower survival rates in gastric adenocarcinoma patients, and Helicobacter pylori infection contributes to tumorigenesis; we asked whether H.

Regulation of Tolerogenic Features on Dexamethasone-Modulated MPLA-Activated Dendritic Cells by MYC.

The potential of tolerogenic dendritic cells (tolDCs) to shape immune responses and restore tolerance has turn them into a promising therapeutic tool for cellular therapies directed toward immune regulation in autoimmunity. Although the cellular mechanisms by which these cells can exert their regulatory function are well-known, the mechanisms driving their differentiation and function are still poorly known, and the variety of stimuli and protocols applied to differentiate DCs toward a tolerogenic phenotype makes it even more complex to underpin the molecular features involved in their function. Through transcriptional profiling analysis of monocyte-derived tolDCs modulated with dexamethasone (Dex) and activated with monophosphoryl lipid A (MPLA), known as DM-DCs, we were able to identify MYC as one of the transcriptional regulators of several genes differentially expressed on DM-DCs compared to MPLA-matured DCs (M-DCs) and untreated/immature DCs (DCs) as revealed by Ingenuity Pathway Analysis (IPA) upstream regulators evaluation.

Interplay Between the Unfolded Protein Response and Immune Function in the Development of Neurodegenerative Diseases.

Emerging evidence suggests that the immune and nervous systems are in close interaction in health and disease conditions. Protein aggregation and proteostasis dysfunction at the level of the endoplasmic reticulum (ER) are central contributors to neurodegenerative diseases. The unfolded protein response (UPR) is the main transduction pathway that maintains protein homeostasis under conditions of protein misfolding and aggregation.

Dexamethasone and Monophosphoryl Lipid A Induce a Distinctive Profile on Monocyte-Derived Dendritic Cells through Transcriptional Modulation of Genes Associated With Essential Processes of the Immune Response.

There is growing interest in the use of tolerogenic dendritic cells (tolDCs) as a potential target for immunotherapy. However, the molecular bases that drive the differentiation of monocyte-derived DCs (moDCs) toward a tolerogenic state are still poorly understood. Here, we studied the transcriptional profile of moDCs from healthy subjects, modulated with dexamethasone (Dex) and activated with monophosphoryl lipid A (MPLA), referred to as Dex-modulated and MPLA-activated DCs (DM-DCs), as an approach to identify molecular regulators and pathways associated with the induction of tolerogenic properties in tolDCs.

A functional IL1RL1 variant regulates corticosteroid-induced sST2 expression in ulcerative colitis.

The ST2/IL33 signalling pathway has been associated with ulcerative colitis (UC). ST2, encoded by the IL1RL1 gene, is expressed as both a membrane-anchored receptor (ST2L) activated by IL33 and as a soluble receptor (sST2) with anti-inflammatory properties. In UC patients, sST2 is further increased by corticosteroid treatment; however, the glucocorticoid-mediated molecular regulation remains unknown.

Treatment with Dexamethasone and Monophosphoryl Lipid A Removes Disease-Associated Transcriptional Signatures in Monocyte-Derived Dendritic Cells from Rheumatoid Arthritis Patients and Confers Tolerogenic Features.

Tolerogenic dendritic cells (TolDCs) are promising tools for therapy of autoimmune diseases, such as rheumatoid arthritis (RA). Here, we characterize monocyte-derived TolDCs from RA patients modulated with dexamethasone and activated with monophosphoryl lipid A (MPLA), referred to as MPLA-tDCs, in terms of gene expression, phenotype, cytokine profile, migratory properties, and T cell-stimulatory capacity in order to explore their suitability for cellular therapy. MPLA-tDCs derived from RA patients displayed an anti-inflammatory profile with reduced expression of co-stimulatory molecules and high IL-10/IL-12 ratio, but were capable of migrating toward the lymphoid chemokines CXCL12 and CCL19.

Tolerogenic dendritic cells for reprogramming of lymphocyte responses in autoimmune diseases.

Dendritic cells (DCs) control immune responses by driving potent inflammatory actions against external and internal threats while generating tolerance to self and harmless components. This duality and their potential to reprogram immune responses in an antigen-specific fashion have made them an interesting target for immunotherapeutic strategies to control autoimmune diseases. Several protocols have been described for in vitro generation of tolerogenic DCs (tolDCs) capable of modulating adaptive immune responses and restoring tolerance through different mechanisms that involve anergy, generation of regulatory lymphocyte populations, or deletion of potentially harmful inflammatory T cell subsets.

Gene Expression Profiling of Human Monocyte-derived Dendritic Cells - Searching for Molecular Regulators of Tolerogenicity.

The ability of dendritic cells (DCs) to initiate and modulate antigen-specific immune responses has made them attractive targets for immunotherapy. Since DC research in humans is limited by the scarcity of DC populations in the blood circulation, most of our knowledge about DC biology and function has been obtained in vitro from monocyte-derived DCs (moDCs), which can be readily generated in sufficient numbers and are able to differentiate into distinct functional subsets depending on the nature of stimulus. In particular, moDCs with tolerogenic properties (tolDCs) possess great therapeutic potential for the treatment of autoimmune diseases.

Skewing dendritic cell differentiation towards a tolerogenic state for recovery of tolerance in rheumatoid arthritis.

To date, the available options to treat autoimmune diseases such as rheumatoid arthritis (RA) include traditional corticoids and biological drugs, which are not exempt of adverse effects. The development of cellular therapies based on dendritic cells with tolerogenic functions (TolDCs) has opened a new possibility to efficiently eradicate symptoms and control the immune response in the field of autoimmunity. TolDCs are an attractive tool for antigen-specific immunotherapy to restore self-tolerance in RA and other autoimmune disorders.

A short protocol using dexamethasone and monophosphoryl lipid A generates tolerogenic dendritic cells that display a potent migratory capacity to lymphoid chemokines.

Background: Generation of tolerogenic dendritic cells (TolDCs) for therapy is challenging due to its implications for the design of protocols suitable for clinical applications, which means not only using safe products, but also working at defining specific biomarkers for TolDCs identification, developing shorter DCs differentiation methods and obtaining TolDCs with a stable phenotype. We describe here, a short-term protocol for TolDCs generation, which are characterized in terms of phenotypic markers, cytokines secretion profile, CD4+ T cell-stimulatory ability and migratory capacity.

Methods: TolDCs from healthy donors were generated by modulation with dexamethasone plus monophosphoryl lipid A (MPLA-tDCs).

Blocking of p38 and transforming growth factor β receptor pathways impairs the ability of tolerogenic dendritic cells to suppress murine arthritis.

Objective: Dendritic cells (DCs) modulated with lipopolysaccharide (LPS) are able to reduce inflammation when therapeutically administered into mice with collagen-induced arthritis (CIA). The aim of this study was to uncover the mechanisms that define the tolerogenic effect of short-term LPS-modulated DCs on CIA.

Methods: Bone marrow-derived DCs were stimulated for 4 hours with LPS and characterized for their expression of maturation markers and their cytokine secretion profiles.