Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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ATAC-seq analysis of LPS-trained bone marrow derived macrophages (BMDMs) from WT and SLC1A5_var transgenic mice.

ABSTRACT: The aim of this study is to evaluate the changes in the chromatin accessibility landscape of BMDMs from WT and SLC1A5_var transgenic mice after low-dose LPS training. We compared the data of ATAC-seq performed on nuclei extracted from naive and trained BMDM from both genotypes. Inter-group comparisons revealed differentially accessible regions to occur between traind WT and Tg BMDMs. Since SLC1A5_var function as unique mitochondrial glutamine transporter, the results indicate that altered glutaminolysis could impact chromatin accessbility.

INSTRUMENT(S): Illumina NovaSeq X

ORGANISM(S): Mus musculus

SUBMITTER: Ya Chun Yu

PROVIDER: E-MTAB-16191 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Reticuloendothelial macrophages engulf ~0.2 trillion senescent erythrocytes daily in a process called erythrophagocytosis (EP). This critical mechanism preserves systemic heme-iron homeostasis by regulating red blood cell (RBC) catabolism and iron recycling. Although extensive work has demonstrated the various effects on macrophage metabolic reprogramming by stimulation with proinflammatory cytokines, little is known about the impact of EP on the macrophage metabolome and proteome. Thus, we performed mass spectrometry-based metabolomics and proteomics analyses of bone marrow-derived macrophages (BMDMs) before and after EP of IgG-coated RBCs. Further, metabolomics was performed on BMDMs incubated with free IgG to ensure that changes to macrophage metabolism were due to opsonized RBCs and not to free IgG binding. Uniformly labeled tracing experiments were conducted on BMDMs in the presence and absence of IgG-coated RBCs to assess the flux of glucose through the pentose phosphate pathway (PPP). In this study, we demonstrate that EP significantly alters amino acid and fatty acid metabolism, the Krebs cycle, OXPHOS, and arachidonate-linoleate metabolism. Increases in levels of amino acids, lipids and oxylipins, heme products, and RBC-derived proteins are noted in BMDMs following EP. Tracing experiments with U-13C6 glucose indicated a slower flux through glycolysis and enhanced PPP activation. Notably, we show that it is fueled by glucose derived from the macrophages themselves or from the extracellular media prior to EP, but not from opsonized RBCs. The PPP-derived NADPH can then fuel the oxidative burst, leading to the generation of reactive oxygen species necessary to promote digestion of phagocytosed RBC proteins via radical attack. Results were confirmed by redox proteomics experiments, demonstrating the oxidation of Cys152 and Cys94 of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and hemoglobin-β, respectively. Significant increases in early Krebs cycle and C5-branched dibasic acid metabolites (α-ketoglutarate and 2-hydroxyglutarate, respectively) indicate that EP promotes the dysregulation of mitochondrial metabolism. Lastly, EP stimulated aminolevulinic acid (ALA) synthase and arginase activity as indicated by significant accumulations of ALA and ornithine after IgG-mediated RBC ingestion. Importantly, EP-mediated metabolic reprogramming of BMDMs does not occur following exposure to IgG alone. In conclusion, we show that EP reprograms macrophage metabolism and modifies macrophage polarization.

Dataset Information

ATAC-seq analysis of LPS-trained bone marrow derived macrophages (BMDMs) from WT and SLC1A5_var transgenic mice.

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