A defective pentose phosphate pathway reduces inflammatory macrophage responses during hypercholesterolemia
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA420032 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6326090.fastq.gz | Fastqsanger.gz | |||
| SRR6326100.fastq.gz | Fastqsanger.gz | |||
| SRR6326091.fastq.gz | Fastqsanger.gz | |||
| SRR6326092.fastq.gz | Fastqsanger.gz | |||
| SRR6326093.fastq.gz | Fastqsanger.gz |
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Project description:Metabolic reprogramming has emerged as a crucial regulator of immune cell activation but how systemic metabolism influences immune cell metabolism and function remains to be investigated. To investigate the effect of dyslipidemia on immune cell metabolism, we performed in-depth transcriptional, metabolic and functional characterization of macrophages isolated from hypercholesterolemic mice. Systemic metabolic changes in such mice alter cellular macrophage metabolism and attenuate inflammatory macrophage responses. In addition to diminished maximal mitochondrial respiration, hypercholesterolemia reduces the LPS-mediated induction of the pentose phosphate pathway (PPP) and the Nrf2-mediated oxidative stress response. Our observation that suppression of the PPP diminishes LPS-induced cytokine secretion supports the notion that this pathway contributes to inflammatory macrophage responses. Overall, this study reveals that systemic and cellular metabolism are strongly interconnected, together dictating macrophage phenotype and function.
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Project description:During early pregnancy, glucose is essential for the uterine epithelium and the developing embryo. In cows, studies have shown that progesterone increases the secretion of glucose into the uterine lumen. Nevertheless, how progesterone affects glucose metabolism in the uterine epithelium has been sparsely investigated. Therefore, our objective was to investigate how progesterone influences glucose metabolism in immortalized bovine uterine epithelial (BUTE) cells. Progesterone treatment (10 μM) increased glucose consumption. To gain a more global picture of the effects of progesterone, RNAseq was performed after BUTE cells were treated with vehicle (DMSO) or 10 μM for 24 hours. KEGG analysis indicated that progesterone altered genes associated with metabolic pathways and glutathione metabolism. Manually examining genes unique to specific glucose metabolic pathways identified an increase in the rate-limiting enzyme in the pentose phosphate pathway—glucose-6-phosphate dehydrogenase. Functionally, a major product of the pentose phosphate pathway is NADPH, and progesterone treatment increased NADPH concentrations in BUTE cells. In cows, immunohistochemistry confirmed that glucose-6-phosphate dehydrogenase levels were higher in the uterine epithelium in the luteal phase when progesterone concentrations are high. In conclusion, progesterone increased glucose-6-phosphate dehydrogenase expression and metabolism via the pentose phosphate pathway in the bovine uterine epithelium. This metabolism could provide substrates for cell proliferation, molecules to be secreted into the uterine lumen that supports embryonic development, or maintain reduction/oxidation balance in the uterine epithelium.
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Project description:Here, gene profiles in rat spermatogonial stem cell lines are compared to publicly available mouse, monkey and human spermatogonial gene profiles. Interestingly, rat spermatogonia expressed metabolic control factors Foxa1, Foxa2 and Foxa3. Germline Foxa2 was enriched in Gfra1Hi and Gfra1Low undifferentiated A-single spermatogonia. Foxa2-bound loci in spermatogonial chromatin were over-represented by conserved stemness genes (Dusp6, Gfra1, Etv5, Rest, Nanos2, Foxp1) that intersect bioinformatically with conserved glutathione/pentose phosphate metabolism genes (Tkt, Gss, Gclc, Gclm, Gpx1, Gpx4, Fth), marking elevated spermatogonial GSH:GSSG. Cystine-uptake and intracellular conversion to cysteine typically couple glutathione biosynthesis to pentose phosphate metabolism. Rat spermatogonia, curiously, displayed poor germline stem cell viability in cystine-containing media, and, like primate spermatogonia, exhibited reduced transsulfuration pathway markers. Exogenous cysteine, cysteine-like mercaptans, somatic testis cells and ferroptosis inhibitors counteracted the cysteine starvation-induced spermatogonial death and stimulated spermatogonial growth factor activity in vitro.
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Project description:IRG1/itaconate axis modulates lung tumor microenvironment via pentose phosphate pathway
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Project description:Engineering the pentose phosphate pathway in Saccharomyces cerevisiae using an evolutionary engineering based strategy.
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Project description:IRG1/itaconate axis modulates lung tumor microenvironment via pentose phosphate pathway [sav25]
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Project description:IRG1/itaconate axis modulates lung tumor microenvironment via pentose phosphate pathway [sav24]
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Project description:Tumor-associated macrophages (TAMs) are an important component of the immune milieu within the lung tumor microenvironment (TME) and have both tumor-promoting and tumor-inhibiting functions. However, the exact mechanisms underlying TAM-mediated inhibition of tumor development are still unknown. Itaconate is one of the main metabolites produced by the enzyme immune responsive gene 1 (IRG1) during a pro-inflammatory response. Single cell RNA-seq studies show that macrophages are the major immune cells for Irg1 expression in human and mouse lung tumors. Both Irg1-deficient mice and transplantation of Irg1-depleted bone marrow resulted in increased development of lung tumors in Kras and orthotopic mouse models, suggesting the anti-tumor function of Irg1-associated macrophages. On the other hand, 4-octyl-itaconate (octyl-Ita) reduces lung tumor development in lung cancer cell lines in vitro, in vivo models of lung cancer, and ex vivo using human tumor precision-cut lung slices. Mechanistically, IRG1/itaconate induces a metabolic shift in cancer cells and pro-tumor macrophages, specifically through inhibition of the pentose phosphate pathway (PPP). An integrative analysis of metabolomics, transcriptomics and proteomics identified glucose-6-phosphate dehydrogenase (G6PD) as the primary target for the antiproliferative effect of IRG1/itaconate. IRG1/Itaconate inhibited G6PD activity without affecting G6PD expression in Irg1-deficient mice and octyl Ita-treated lung cancer models. The novel inhibitory effects of IRG1/Itaconate and Octyl Ita on G6PD activity and PPP metabolism can not only suppress cancer cell proliferation in a non-cell-autonomous manner, but also re-educate pro-tumor macrophages into anti-tumor macrophages in a cell-autonomous manner. Our results suggest that octyl Ita is an effective anti-tumor metabolite with potential therapeutic application in lung cancer.
2026-06-11 | GSE256044 | GEO
Project description:Tumor-associated macrophages (TAMs) are an important component of the immune milieu within the lung tumor microenvironment (TME) and have both tumor-promoting and tumor-inhibiting functions. However, the exact mechanisms underlying TAM-mediated inhibition of tumor development are still unknown. Itaconate is one of the main metabolites produced by the enzyme immune responsive gene 1 (IRG1) during a pro-inflammatory response. Single cell RNA-seq studies show that macrophages are the major immune cells for Irg1 expression in human and mouse lung tumors. Both Irg1-deficient mice and transplantation of Irg1-depleted bone marrow resulted in increased development of lung tumors in Kras and orthotopic mouse models, suggesting the anti-tumor function of Irg1-associated macrophages. On the other hand, 4-octyl-itaconate (octyl-Ita) reduces lung tumor development in lung cancer cell lines in vitro, in vivo models of lung cancer, and ex vivo using human tumor precision-cut lung slices. Mechanistically, IRG1/itaconate induces a metabolic shift in cancer cells and pro-tumor macrophages, specifically through inhibition of the pentose phosphate pathway (PPP). An integrative analysis of metabolomics, transcriptomics and proteomics identified glucose-6-phosphate dehydrogenase (G6PD) as the primary target for the antiproliferative effect of IRG1/itaconate. IRG1/Itaconate inhibited G6PD activity without affecting G6PD expression in Irg1-deficient mice and octyl Ita-treated lung cancer models. The novel inhibitory effects of IRG1/Itaconate and Octyl Ita on G6PD activity and PPP metabolism can not only suppress cancer cell proliferation in a non-cell-autonomous manner, but also re-educate pro-tumor macrophages into anti-tumor macrophages in a cell-autonomous manner. Our results suggest that octyl Ita is an effective anti-tumor metabolite with potential therapeutic application in lung cancer.
2026-06-11 | GSE256041 | GEO
Project description:Metabolic pathways are now considered as intrinsic virulence attributes of pathogenic bacteria and hence represent potential targets for anti-bacterial strategies. Here, we addressed the role of the pentose phosphate pathway (PPP) and its connections with other metabolic pathways in the pathophysiology of Francisella novicida. We have previously shown that this intracellular bacterial pathogen used gluconeogenesis to metabolize host-derived nutrients in the cytosolic compartment of infected macrophages. Francisella species, which lacks the oxidative branch of the PPP, are equipped with all the genes of the non-oxidative branch (i.e. tktA, tal, rpiA and rpe, encoding transketolase, transaldolase, ribose-phosphate isomerase and ribulose phosphate epimerase, respectively). The involvement of the PPP in the early stage of intracellular life cycle of F. novicida was first demonstrated with the study of PPP inactivation mutants. Indeed, inactivation of tktA, rpiA or rpe genes, severely impaired intramacrophagic multiplication during the first 24–hours. However, time-lapse video microscopy demonstrated that rpiA and rpe mutants were able to resume late intracellular bacterial multiplication. To get further insight into the links between the PPP and other metabolic networks of the bacterium, we next performed a thorough proteo-metabolomic analysis of these mutants. We show that the PPP constitutes a major bacterial metabolic hub with multiple connections with glycolysis, tricarboxylic acid cycle and other metabolic pathways, such as fatty acid degradation and sulfur metabolism. Hence, our study highlights how, by its multiple connections with other metabolic pathways, PPP is instrumental to Francisella pathogenesis and growth in its intracellular niche.
2021-07-27 | PXD023550 | Pride