TGF-β uncouples glycolysis and inflammation in macrophages and controls the survival during sepsis [LPS]
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ABSTRACT:
PROVIDER: PRJNA923448 | ENA |
REPOSITORIES: ENA
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Project description:The mechanisms by which macrophage metabolism is regulated and the effects of metabolism on diseases remain largely unknown. We show here that TGF-β regulates the glycolysis of macrophages independently of inflammatory cytokine production, and thus affects the survival in experimental sepsis. Specifically, TGF-β increased expression and activity of phosphofructokinase-1 liver type (PFKL) in macrophages and thus promoted their glycolysis during cell activation, yet paradoxically suppressed the production of proinflammatory cytokines in the same macrophages. The upregulation of glycolysis was mediated by a mTOR-c-MYC dependent pathway, whereas the inhibition of cytokines was ascribed to the activation of SMAD3 and a downregulated activation of the pro-inflammatory transcription factors AP-1, NFkB and STAT1. Importantly, in an LPS-induced sepsis model, TGF-β enhancement of macrophage glycolysis led to a decreased survival in mice, which was associated with increased blood coagulation. Analysis of cohorts of patients with sepsis and covid-19 revealed that the expression of PFKL, TGF-b receptors TGFBRI and coagulation factor F13A1 in myeloid cells positively correlated with the progression of the disease. Thus, TGF-β is emerging as a critical cytokine regulating macrophage metabolism and could serve as a therapeutic target in patients with sepsis.
2023-08-14 | GSE222805 | GEO
Project description:The mechanisms by which macrophage metabolism is regulated and the effects of metabolism on diseases remain largely unknown. We show here that TGF-β regulates the glycolysis of macrophages independently of inflammatory cytokine production, and thus affects the survival in experimental sepsis. Specifically, TGF-β increased expression and activity of phosphofructokinase-1 liver type (PFKL) in macrophages and thus promoted their glycolysis during cell activation, yet paradoxically suppressed the production of proinflammatory cytokines in the same macrophages. The upregulation of glycolysis was mediated by a mTOR-c-MYC dependent pathway, whereas the inhibition of cytokines was ascribed to the activation of SMAD3 and a downregulated activation of the pro-inflammatory transcription factors AP-1, NFkB and STAT1. Importantly, in an LPS-induced sepsis model, TGF-β enhancement of macrophage glycolysis led to a decreased survival in mice, which was associated with increased blood coagulation. Analysis of cohorts of patients with sepsis and covid-19 revealed that the expression of PFKL, TGF-b receptors TGFBRI and coagulation factor F13A1 in myeloid cells positively correlated with the progression of the disease. Thus, TGF-β is emerging as a critical cytokine regulating macrophage metabolism and could serve as a therapeutic target in patients with sepsis.
2023-08-14 | GSE222826 | GEO
Project description:The mechanisms by which macrophage metabolism is regulated and the effects of metabolism on diseases remain largely unknown. We show here that TGF-β regulates the glycolysis of macrophages independently of inflammatory cytokine production, and thus affects the survival in experimental sepsis. Specifically, TGF-β increased expression and activity of phosphofructokinase-1 liver type (PFKL) in macrophages and thus promoted their glycolysis during cell activation, yet paradoxically suppressed the production of proinflammatory cytokines in the same macrophages. The upregulation of glycolysis was mediated by a mTOR-c-MYC dependent pathway, whereas the inhibition of cytokines was ascribed to the activation of SMAD3 and a downregulated activation of the pro-inflammatory transcription factors AP-1, NFkB and STAT1. Importantly, in an LPS-induced sepsis model, TGF-β enhancement of macrophage glycolysis led to a decreased survival in mice, which was associated with increased blood coagulation. Analysis of cohorts of patients with sepsis and covid-19 revealed that the expression of PFKL, TGF-b receptors TGFBRI and coagulation factor F13A1 in myeloid cells positively correlated with the progression of the disease. Thus, TGF-β is emerging as a critical cytokine regulating macrophage metabolism and could serve as a therapeutic target in patients with sepsis.
2023-08-14 | GSE222804 | GEO
Project description:<p>The mechanisms by which macrophage metabolism is regulated and the effects of metabolism on diseases remain largely unknown. We show here that TGF-β regulates the glycolysis of macrophages independently of inflammatory cytokine production, and thus affects the survival in experimental sepsis. Specifically, TGF-β increased expression and activity of phosphofructokinase-1 liver type (PFKL) in macrophages and thus promoted their glycolysis during cell activation, yet paradoxically suppressed the production of proinflammatory cytokines in the same macrophages. The upregulation of glycolysis was mediated by a mTOR-c-MYC dependent pathway, whereas the inhibition of cytokines was ascribed to the activation of SMAD3 and a downregulated activation of the pro-inflammatory transcription factors AP-1, NFkB and STAT1. Importantly, in an LPS-induced endotoxemia and CLP-sepsis models, TGF-β enhancement of macrophage glycolysis led to a decreased survival in mice, which was associated with increased blood coagulation. Analysis of cohorts of patients with sepsis and covid-19 revealed that the expression of PFKL, TGF-β receptor TGFBRI and coagulation factor F13A1 in myeloid cells positively correlated with the progression of the disease. Thus, TGF-β is emerging as a critical cytokine regulating macrophage metabolism and could serve as a therapeutic target in patients with sepsis.</p>
2023-02-17 | MTBLS6886 | MetaboLights
Project description:TGF-β uncouples glycolysis and inflammation in macrophages and controls the survival during sepsis
| PRJNA923615 | ENA
Project description:TGF-β uncouples glycolysis and inflammation in macrophages and controls the survival during sepsis [STIM]
| PRJNA923626 | ENA
Project description:TGF-β uncouples glycolysis and inflammation in macrophages and controls the survival during sepsis [ATAC-Seq]
| PRJNA923447 | ENA
Project description:Sepsis-induced liver dysfunction is a frequent event and is strongly associated with mortality. Establishing a causative link between protein post-translational modification (PTM) and diseases is challenging. We studied the relationship among the lysine acetylation (Kac), the sirtuin (SIRTs), and their interactors carefully selected in sepsis-induced liver dysfunction (SILD), per-formed on LPS-stimulated HepG2 cells. Protein hyperacetylation was observed according to SIRTs reduction after LPS treatment for 24 h. We identified 1,449 Kac sites based on comparative acetylome analysis, and quantified 1,086 Kac sites on 410 proteins for acetylation. Interestingly, the up-regulated Kac proteins are enriched in glycolysis/gluconeogenesis pathways in the KEGG category. Among the proteins in the glycolysis pathway, hyperacetylation, a key regulator of lactate level in sepsis, was observed in three pyruvate kinase M2 (PKM2) sites. Hyperacetylation of PKM2 induced an increase in its activity, increasing the lactate concentration as a result. In conclusion, this study is the first to conduct global profiling of Kac, suggesting the Kac mecha-nism of PKM2 in glycolysis of sepsis. Moreover, it helps further understand the systematical in-formation of hyperacetylation during the sepsis process.
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Project description:To check changes in transcriptome in whole brain upon LPS sepsis, mice were injected with PBS or LPS and gene expression was analyzed. Nav1.8CreROSA26DTA mice lack Nav1.8-positive nociceptor.
2022-12-20 | GSE173216 | GEO
Project description:Sepsis is a life-threatening organ dysfunction resulting from a dysregulated host response to infection. This is best studied in humans and various mouse models, however finding sof these models to not always translate easy to the clinic. In order to improve this transfer, and because sepsis also plays a significant role in vetrenairy medicine, we use the pig as a model organism in sepsis research. We compare two modes of porcine sepsis iduction: fecal infusion and LPS infusion and also compare thse o wha we can find in mice
2023-12-31 | GSE250039 | GEO