Homo sapiens
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PROVIDER: PRJNA313233 | ENA |
REPOSITORIES: ENA
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Project description:Recent studies have demonstrated that upon encountering a pathogenic stimulus, robust metabolic rewiring of immune cells occurs. A switch away from oxidative phosphorylation to glycolysis, even in the presence of sufficient amounts of oxygen (akin the Warburg effect), is typically observed in activated innate and adaptive immune cells and is thought to accommodate adequate inflammatory responses. However, whether the Warburg effect is a general phenomenon applicable in human monocytes exposed to different pathogenic stimuli is unknown. Our results using human monocytes from healthy donors demonstrate that the Warburg effect only holds true for TLR4 activated cells. Although activation of other TLRs leads to an increase in glycolysis, no reduction or even an enhancement in oxidative phosphorylation is observed. Moreover, specific metabolic rewiring occurs in TLR4 vs. TLR2 stimulated cells characterized by altered gene expression profiles of pathways related to metabolism, changes in spare respiratory capacity of the cells and differential regulation of mitochondrial enzyme activity. Similarly, results from ex vivo and in vivo studies demonstrate metabolic rewiring of immune cells that is highly dependent on the type of pathogenic stimulus. Although the Warburg effect is observed in human monocytes after TLR4 activation, we propose that this typical metabolic response is not applicable to other inflammatory signalling routes including TLR2 in human monocytes. Instead, each pathogenic stimulus and subsequently activated inflammatory signalling cascade induces specific metabolic rewiring of the immune cell to accommodate an appropriate response.
2016-10-19 | GSE78699 | GEO
Project description:The current view of cellular transformation and cancer progression supports the notion that cancer cells must reprogram their metabolism in order to survive and progress in different microenvironments. Master co-regulators of metabolism orchestrate the modulation of multiple metabolic pathways through transcriptional programs, and hence constitute a probabilistically parsimonious mechanism for general metabolic rewiring. Here we show that the transcriptional co-activator PGC1α suppresses prostate cancer progression and metastasis. A metabolic co-regulator data mining analysis unveiled that PGC1α is consistently down-regulated in multiple prostate cancer patient datasets and its alteration is associated with reduced disease-free survival and metastasis. Genetically engineered mouse model studies revealed that compound prostate epithelium-specific deletion of Pgc1a and Pten promotes prostate cancer progression and metastasis, whereas, conversely, PGC1α expression in cell lines inhibits the pre-existing metastatic capacity. Through the application of integrative metabolomics and transcriptomics we demonstrate that PGC1α expression in prostate cancer is sufficient to elicit a global metabolic rewiring that opposes cell growth, consisting of sustained oxidative metabolism at the expense of anabolism. This metabolic program is regulated downstream the Oestrogen-related receptor alpha (ERRα), and PGC1α mutants lacking ERRα activation capacity lack metabolic rewiring capacity and metastasissuppressive function. Importantly, an ERRα signature in prostate cancer recapitulates the prognostic features of PGC1A. Our findings uncover an unprecedented causal contribution of PGC1α to the metabolic switch in prostate cancer and to the suppression of metastatic dissemination. Total RNA was isolated from prostate cancer cell line PC3 expressing or not PGC1a (for induction, cells were treated with doxycycline for 2 passages)
2016-03-16 | E-GEOD-75193 | biostudies-arrayexpress
Project description:The dataset includes raw RNA-seq data (fastq files) for miRNAs of monocytes before and after 6-hour exposure to four different immune stimuli, measured in 200 African- and European-descent healthy donors from Belgium. The stimuli include ligands for TLR4 (LPS), TLR1/2 (Pam3CSK4) and TLR7/8 (R848) and to a human seasonal influenza A virus (IAV).
| EGAD00001006181 | EGA
Project description:In recent years, it has been recognized the central role of cell bioenergetics in regulating immune cell function and fate giving rise to the interest in immunometabolism, an area of research focused on the interaction between metabolic regulation and immune function. Immunometabolism has been studied in the modulation of macrophage polarization. Thus, early metabolic changes associated with the polarisation of macrophages into pro-inflammatory or pro-resolving cells under different stimuli have been characterized. Tumour-associated macrophages are among the most abundant cells in the tumour microenvironment; however, it exists an unmet need to study the effect of chemotherapeutics on macrophage immunometabolism. Here, a systems biology approach that integrates transcriptomics and metabolomics unveils the immunometabolic effects of trabectedin (TRB) and lurbinectedin (LUR), two intercalating DNA agents with proved antitumor activity in the low nanomolar range. Our results show that TRB and LUR activate human macrophages towards a pro-inflammatory functional phenotype by inducing a specific metabolic rewiring program that includes ROS production and changes in the mitochondrial inner membrane potential, increased pentose phosphate pathway, TCA cycle serine and methylglyoxal pathways in human macrophages. glutamine, aspartate, histidine, and proline consumption are increased whereas 50 nM TRB increases lactate release and oxygen consumption is depressed . The observed immunometabolic rewiring could explain additional antitumor activities of these compounds and open new avenues to design therapeutic interventions that specifically target the immunometabolic landscape in the treatment of cancer.
2023-06-25 | GSE235390 | GEO
Project description:Extracellular vesicles play an important role in human cellular communication. Here, we show that human and mouse monocytes release TGF-β1-transporting vesicles in response to the pathogenic fungus Candida albicans. Soluble beta-glucan from Candida albicans binds to complement receptor 3 (CR3, CD11b/CD18) on monocytes and induces the release of TGF-β1-transporting vesicles. CR3-dependence is demonstrated using CR3-deficient (CD11b knockout) monocytes generated by CRISPR-CAS9 genome editing and isolated from CR3-deficient (CD11b knockout) mice. Isolated vesicles dampen the pro-inflammatory response in human M1-macrophages as well as in whole blood. Binding of the vesicle-transported TGF-β1 to the TGF-β receptor inhibits IL-1β gene transcription via the SMAD7 pathway in whole blood and induces TGF-β1 transcription in endothelial cells. Inhibition of TGF-β1 relieved the suppression of such proinflammatory effect. Notably, human opsonized apoptotic bodies induce similar TGF-β1-transporting vesicles in monocytes, suggesting that the early immune response is suppressed through this newly identified CR3-dependent anti-inflammatory vesicle pathway.
2020-04-22 | PXD015780 | Pride
Project description:Goal of this study was to determine metabolic adaptation processes in C. albicans associated to hyphal morphogenesis. Accessory to the metabolic profiling the corresponding transcriptome was investigated. To identify media-specific and general adaptation three different hyphae stimuli were used (M199 pH 7.4, Human serum and N-Aectylglucosamine) were used and compared again two respective yeast conditions (SD and M199 pH 4). Two filamentation-affected mutant strains were included - lacking either two central regulators of filamentation (cph1Δ/efg1Δ) or a downstream effector (hgc1Δ) - for the identification of specfic morphotype-dependent metabolic adaptation in repsonse to hyphae stimuli. Two different time points (90 min and 240 min after transition to test medium) were investigated to define the progression of the examined adaptation processes.
2022-10-14 | GSE202941 | GEO
Project description:Macrophages must rapidly shift their cellular metabolism to facilitate the induction of the proinflammatory response, including activation of lipid synthesis pathways. However, the links between lipid metabolism and polarization in response to inflammatory signals remains unclear. Acetyl-CoA Carboxylase (ACC) is central to lipid synthesis, cellular energy utilization, and acetylation-dependent enzyme activation, but its role in macrophages remains unclear. To interrogate the role of ACC in the inflammatory response, we generated myeloid-specific LysMCre Acacafl/fl Acacbfl/fl ACC double knockout (ACCLysM) mice. Unexpectedly, myeloid-specific deletion or pharmacological inhibition of ACC attenuated lipopolysaccharide (LPS)-induced inflammation in mice, with decreased gene expression and protein levels of the proinflammatory cytokines IL-6 and IL-1. Using in vitro transcriptomics, lipidomics, and bioenergetics approaches we find that ACC deletion reestablishes the metabolic setpoint in macrophages and is required for metabolic rewiring in response to LPS- but not IL-4-dependent signaling. This translated to blunted phenotypic polarization to proinflammatory but not alternatively activating stimuli. Mechanistically, we identified that the metabolic rewiring that results from ACC deletion increased basal acetylation at histone H3 lysine 27 (H3K27Ac), a marker of active enhancers, which was reduced in response to LPS in ACC-deficient BMDMs. The failure of macrophages lacking ACC to adapt their glycolytic metabolism and polarize to inflammatory stimuli impaired macrophage proinflammatory effector functions. Taken together these data identify a novel role for ACC in metabolic and transcriptional regulation of the acute inflammatory response.
2023-01-04 | GSE193294 | GEO
Project description:Trained immunity is a form of innate immune memory characterized by epigenetic and metabolic reprogramming in response to specific stimuli. This rewiring can result in increased cytokine and effector responses to pathogenic challenge, providing non-specific protection against disease. It may also improve immune responses to established immunotherapeutics and vaccines. Despite the promise of training for next-generation therapeutic design, most current understanding and experimentation is conducted with complex and heterogeneous biologically derived molecules, such as β-glucan or the BCG vaccine. This limited collection of training compounds also limits study of the genes most involved in training responses as each molecule has both training and non-training effects. Small molecules with tunable pharmacokinetics and delivery modalities would both assist in the study of trained immunity and its future application for therapeutics. To identify novel small molecule inducers of trained immunity, we screened a library of 2000 drugs and drug-like compounds. Identification of well-defined compounds can improve our understanding of innate immune memory and broaden the scope of its clinical applications. We identified over 2 dozen small molecules in several chemical classes, including the traditionally immunosuppressive glucocorticoids, that induce a training phenotype in the absence of initial immune activation – a current limitation of reported inducers of training. We chose 7 of these top candidates to characterize and establish training activity in vivo. In this work, we expand the number of compounds known to induce trained immunity, creating new avenues for the study and application of innate immune training.
2024-07-08 | GSE270608 | GEO
Project description:The intent of the experiment is to study the reactivity of human primary blood monocytes during a physiological or pathological inflammation. We designed two in vitro models that recapitulate the different phases of the reaction (recruitment, initiation, development, and resolution - \\"resolving model\\" - vs. persistence of inflammation \"persistent model): monocytes were exposed to different stimuli (microbial molecules, cytokines, and Immune complexes), and to sequential changes in microenvironmental conditions (temperature, hypoxia, amount of serum), at different time points (0, 4, 14, 24, 48 h for the resolving model and 0, 2, 4, 14, 24, 72, 96 h for the persistent model).
2020-06-30 | E-MTAB-8226 | biostudies-arrayexpress
Project description:Disruptions of Topological Chromatin Domains Causes Pathogenic Rewiring of Gene-Enhancer Interactions [4C-Seq-human]
| PRJNA276692 | ENA