TGF-β uncouples glycolysis and inflammation in macrophages and controls the survival during sepsis [ATAC-Seq]
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ABSTRACT:
PROVIDER: PRJNA923447 | 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 | 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 | 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 | GSE222804 | GEO
Project description:TGF-β uncouples glycolysis and inflammation in macrophages and controls the survival during sepsis
| PRJNA923615 | ENA
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 [LPS]
| PRJNA923448 | ENA
Project description:TGF-β uncouples glycolysis and inflammation in macrophages and controls the survival during sepsis [STIM]
| PRJNA923626 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-08-14 | GSE222828 | GEO
Project description:Background: Sepsis, a leading cause of morbidity and mortality, is not a homogeneous disease but rather a syndrome encompassing many heterogeneous pathophysiologies. Patient factors including genetics predispose to poor outcomes, though current clinical characterizations fail to identify those at greatest risk of progression and mortality. Results: The Community Acquired Pneumonia and Sepsis Outcome Diagnostic study enrolled 1,152 subjects with suspected sepsis. We sequenced peripheral blood RNA of 129 representative subjects with systemic inflammatory response syndrome (SIRS) or sepsis (infection with SIRS), including 78 sepsis survivors and 28 sepsis nonsurvivors, who had previously undergone plasma proteomic and metabolomic profiling. The expression of 338 genes differed between subjects with SIRS and those with sepsis, primarily reflective of immune activation in sepsis. The expression of 1,238 genes differed with sepsis outcome: Nonsurvivors had lower expression of many immune function-related genes. Functional genetic variants associated with sepsis mortality were sought based on a common disease â rare variant hypothesis. VPS9D1, whose expression was increased in sepsis survivors, had a higher burden of missense variants in sepsis survivors, and these were associated with altered expression of 3,799 genes, primarily reflecting Golgi and endosome biology. Conclusions: Host response in sepsis survivors â activation of immune response-related genes â was muted in sepsis nonsurvivors. The association of sepsis survival with robust immune response and presence of missense variants in VPS9D1 warrants replication and further functional studies. We sequenced peripheral blood RNA of 129 representative subjects with systemic inflammatory response syndrome (SIRS, n=23) or sepsis (infection with SIRS), including 78 sepsis survivors and 28 sepsis nonsurvivors, who had previously undergone plasma proteomic and metabolomic profiling.
2015-01-01 | E-GEOD-63042 | biostudies-arrayexpress
Project description:Background: Sepsis, a leading cause of morbidity and mortality, is not a homogeneous disease but rather a syndrome encompassing many heterogeneous pathophysiologies. Patient factors including genetics predispose to poor outcomes, though current clinical characterizations fail to identify those at greatest risk of progression and mortality. Results: The Community Acquired Pneumonia and Sepsis Outcome Diagnostic study enrolled 1,152 subjects with suspected sepsis. We sequenced peripheral blood RNA of 129 representative subjects with systemic inflammatory response syndrome (SIRS) or sepsis (infection with SIRS), including 78 sepsis survivors and 28 sepsis nonsurvivors, who had previously undergone plasma proteomic and metabolomic profiling. The expression of 338 genes differed between subjects with SIRS and those with sepsis, primarily reflective of immune activation in sepsis. The expression of 1,238 genes differed with sepsis outcome: Nonsurvivors had lower expression of many immune function-related genes. Functional genetic variants associated with sepsis mortality were sought based on a common disease – rare variant hypothesis. VPS9D1, whose expression was increased in sepsis survivors, had a higher burden of missense variants in sepsis survivors, and these were associated with altered expression of 3,799 genes, primarily reflecting Golgi and endosome biology. Conclusions: Host response in sepsis survivors – activation of immune response-related genes – was muted in sepsis nonsurvivors. The association of sepsis survival with robust immune response and presence of missense variants in VPS9D1 warrants replication and further functional studies.
2015-01-01 | GSE63042 | GEO