Itaconate mediates an immunometabolic crosstalk between osteoclasts and osteoblasts
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ABSTRACT:
PROVIDER: PRJNA859680 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR20280913.fastq.gz | Fastqsanger.gz | |||
| SRR20280914.fastq.gz | Fastqsanger.gz | |||
| SRR20280915.fastq.gz | Fastqsanger.gz | |||
| SRR20280916.fastq.gz | Fastqsanger.gz | |||
| SRR20280917.fastq.gz | Fastqsanger.gz |
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Project description:Bone remodeling is a highly dynamic process dependent on the precise coordination of osteoblasts and hematopoietic-cell derived osteoclasts. Emerging evidence indicates that cellular differentiation is associated with a metabolic rewiring in conjunction with the acquisition of specific effector functions. Changes in core metabolic pathways during osteoclastogenesis, however, are largely unexplored and it is unknown whether and how these processes are involved in bone homeostasis. We show that during differentiation preosteoclasts rearrange their tricarboxylic acid (TCA) cycle, a process crucially depending on both glucose and glutamine. This rearrangement is characterized by induction of immunoresponsive gene 1 (Irg1) and production of itaconate, which accumulates intra- and extracellularly. While the IRG1-itaconate axis is dispensable for osteoclast generationin vitroandin vivo, we demonstrate that itaconate stimulates osteoblasts by accelerating osteogenic differentiation, reducing proliferation and shifting ATP production from mitochondrial respiration to glycolysis. Additionally, supplementation of itaconate increases bone formation by boosting osteoblast activity in mice. Conversely,Irg1deficient mice exhibit decreased bone mass and have reduced osteoproliferative lesions in experimental arthritis. In summary, we identify itaconate, generated as a result of the metabolic rewiring during osteoclast differentiation, as a previously unrecognized regulator of the crosstalk between osteoclasts and osteoblasts
2024-07-24 | GSE236452 | GEO
Project description:Itaconate mediates a metabolic crosstalk between osteoclasts and osteoblasts
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Project description:In this report, we show that both glucose and glutamine are essential during OC differentiation, and both contribute to the maintenance of the TCA cycle. Early differentiation is associated with a broken TCA cycle, with IRG1 siphoning TCA intermediates for the production of itaconate, which accumulates extracellularly, stimulating the function of osteoblasts in vitro an in vivo and in vivo and is necessary to retain bone mass in mice.
2024-07-14 | GSE208359 | GEO
Project description:The hormone calcitonin (CT) is primarily known for its pharmacologic action as an inhibitor of bone resorption, yet CT-deficient mice display increased bone formation. These findings raised the question about the underlying cellular and molecular mechanism of CT action. Here we show that either ubiquitous or osteoclast-specific inactivation of the murine CT receptor (CTR) causes increased bone formation. CT negatively regulates the osteoclast expression of Spns2 gene, which encodes a transporter for the signaling lipid sphingosine 1-phosphate (S1P). CTR-deficient mice show increased S1P levels, and their skeletal phenotype is normalized by deletion of the S1P receptor S1P3. Finally, pharmacologic treatment with the non-selective S1P receptor agonist FTY720 causes increased bone formation in wildtype, but not in S1P3-deficient mice. This study redefines the role of CT in skeletal biology, confirms that S1P acts as an osteoanabolic molecule in vivo, and provides evidence for a pharmacologically exploitable crosstalk between osteoclasts and osteoblasts. Osteoclasts of wildtype and Calcr-/- C57Bl/6 mice were treated with Calcitonin and compared to the non-treated osteoclasts of wildtype or Calcr-/- mice, respectively.
2014-10-19 | E-GEOD-60761 | biostudies-arrayexpress
Project description:Immune checkpoint blockade (ICB) triggers tumor ferroptosis. However, most patients are unresponsive to ICB. Tumors might evade ferroptosis in the tumor microenvironment (TME). Here, we discovered SLC13A3 is an itaconate transporter in tumor cells and endows tumor ferroptosis resistance, diminishing tumor immunity and ICB efficacy. Mechanistically, tumor cells uptake itaconate via SLC13A3 from tumor-associated macrophages (TAMs), thereby activating the NRF2-SLC7A11 pathway and escaping from immune-mediated ferroptosis. Structural modeling and molecular docking analysis identified a functional inhibitor for SLC13A3 (SLC13A3i). Deletion of ACOD1 (an essential enzyme for itaconate synthesis) in macrophages, genetic ablation of SLC13A3 in tumors, or treatment with SLC13A3i sensitized tumors to ferroptosis, curbed tumor progression, and bolstered ICB effectiveness. Thus, we identify the interplay between tumors and TAMs via the SLC13A3-itaconate-NRF2-SLC7A11 axis as a previously unknown immune ferroptosis resistant mechanism in the TME and SLC13A3 as a promising immunometabolic target and disease indication for treating SLC13A3+cancer.
2024-09-19 | GSE268205 | GEO
Project description:Immune checkpoint blockade (ICB) triggers tumor ferroptosis. However, most patients are unresponsive to ICB. Tumors might evade ferroptosis in the tumor microenvironment (TME). Here, we discovered SLC13A3 is an itaconate transporter in tumor cells and endows tumor ferroptosis resistance, diminishing tumor immunity and ICB efficacy. Mechanistically, tumor cells uptake itaconate via SLC13A3 from tumor-associated macrophages (TAMs), thereby activating the NRF2-SLC7A11 pathway and escaping from immune-mediated ferroptosis. Structural modeling and molecular docking analysis identified a functional inhibitor for SLC13A3 (SLC13A3i). Deletion of ACOD1 (an essential enzyme for itaconate synthesis) in macrophages, genetic ablation of SLC13A3 in tumors, or treatment with SLC13A3i sensitized tumors to ferroptosis, curbed tumor progression, and bolstered ICB effectiveness. Thus, we identify the interplay between tumors and TAMs via the SLC13A3-itaconate-NRF2-SLC7A11 axis as a previously unknown immune ferroptosis resistant mechanism in the TME and SLC13A3 as a promising immunometabolic target and disease indication for treating SLC13A3+cancer.
2024-09-19 | GSE268293 | GEO
Project description:Remodeling of the tricarboxylic acid (TCA) cycle is a metabolic adaptation mechanism accompanying inflammatory macrophage activation. During this process, endogenous metabolites can adopt regulatory roles that govern specific aspects of inflammatory response, as recently shown for succinate, which regulates the downstream pro-inflammatory IL-1β-HIF1a axis. Itaconate is one of the most highly induced metabolites in activated macrophages, yet its functional significance remains unknown. Here, we show that itaconate modulates macrophage metabolism and effector functions via its effect on succinate dehydrogenase, by inhibiting conversion of succinate to fumarate. Through this action, itaconate exerts anti-inflammatory effects when administered in vitro and in vivo during macrophage activation and ischemia-reperfusion injury. Using newly generated Irg1-/- mice, which lack the ability to produce itaconate, we show that endogenous itaconate regulates succinate levels and function, changes in mitochondrial respiration, and inflammatory cytokine production during macrophage activation. These studies highlight itaconate as a major physiological regulator of the global metabolic rewiring and effector functions of inflammatory macrophages. Experiment 1: mature WT BMDM were treated for 12h with 0.25 mM dimethyl itaconate (DI) or vehicle (Unst) and then stimulated with LPS (E. coli 0111:B4; 100 ng/ml, 4h) (DI+LPS; LPS); Experiment 2: mature Irg1-/- BMDM were stimulated with LPS (E. coli 0111:B4; 100 ng/ml) and murine recombinant IFNg (50 ng/ml) for 24h.
2016-07-01 | E-GEOD-82043 | biostudies-arrayexpress
Project description:RNA-seq of prostate cancer cell lines co-culture with osteoblasts or osteoclasts
| PRJNA867319 | ENA
Project description:Effects of polycyclic aromatic hydrocarbons on osteoclasts and osteoblasts in the scales of zebrafish
| PRJNA676042 | ENA
Project description:One primary metabolic manifestation of inflammation is the diversion of cis-aconitate within the tricarboxylic acid (TCA) cycle to synthesize the immunometabolite itaconate. Itaconate is well established to possess immunomodulatory and metabolic effects within myeloid cells and lymphocytes, however, its effects in other organ systems during sepsis remain less clear. Utilizing Irg1 knockout mice that are deficient in synthesizing itaconate, we aimed at understanding the metabolic role of itaconate in the liver and systemically during sepsis. We find itaconate aids in lipid metabolism during sepsis. Specifically, Irg1 KO mice develop a heightened level of hepatic steatosis when induced with polymicrobial sepsis. Proteomics analysis reveal enhanced expression of enzymes involved in fatty acid oxidation in following 4-ocytl itaconate (4-OI) treatment in vitro. Downstream analysis reveals itaconate stabilizes the expression of the mitochondrial fatty acid uptake enzyme CPT1a, mediated by its hypoubiquitination. Chemoproteomic analysis revealed itaconate interacts with proteins involved in protein ubiquitination as a potential mechanism underlying its stabilizing effect on CPT1a. From a systemic perspective, we find itaconate deficiency triggers a hypothermic response following endotoxin stimulation, potentially mediated by brown adipose tissue (BAT) dysfunction. Finally, by use of metabolic cage studies, we demonstrate Irg1 KO mice rely more heavily on carbohydrates versus fatty acid sources for systemic fuel utilization in response to endotoxin treatment. Our data reveal a novel metabolic role of itaconate in modulating fatty acid oxidation during polymicrobial sepsis.
2024-01-29 | PXD047706 | Pride