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Serine Metabolism Orchestrates Macrophage Polarization by Regulating the IGF1–p38 Axis

ABSTRACT: Here we show that suppressing the serine biosynthesis pathway, either by inhibiting the activity of the key enzyme phosphoglycerate dehydrogenase or by exogenous serine and glycine restriction, robustly enhances polarization of interferon-g-activated macrophages (M(IFN-g)) but suppresses that of interleukin-4-activated macrophages (M(IL-4)) both in vitro and in vivo.To further explore its mechanism, we used high-throughput sequencing technology (RNA-seq) to assess gene expression in serine-deficiency or not BMDMs

ORGANISM(S): Mus musculus

PROVIDER: GSE196840 | GEO | 2022/02/19

REPOSITORIES: GEO

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Serine Metabolism Antagonizes Antiviral Innate Immunity Through Preventing ATP6V0d2-mediated YAP Lysosomal Degradation

Project description:Here, we demonstrate that virus-infected macrophages display decreased expression of serine synthesis pathway (SSP) enzymes. Suppressing the SSP key enzyme phosphoglycerate dehydrogenase (PHGDH) by genetic approaches enhanced IFN-b-mediated antiviral innate immunity in vitro and in vivo. To further explore its mechanism, we used high-throughput sequencing technology (RNA-seq) to assess gene expression in PHGDH-deficiency BMDMs and RAW264.7 macrophages.

2021-01-29 | GSE165684 | GEO

Serine metabolism orchestrates macrophage polarization by regulating the IGF1-p38 axis.

Project description:Serine metabolism is reportedly involved in immune cell functions, but whether and how serine metabolism regulates macrophage polarization remain largely unknown. Here, we show that suppressing serine metabolism, either by inhibiting the activity of the key enzyme phosphoglycerate dehydrogenase in the serine biosynthesis pathway or by exogenous serine and glycine restriction, robustly enhances the polarization of interferon-γ-activated macrophages (M(IFN-γ)) but suppresses that of interleukin-4-activated macrophages (M(IL-4)) both in vitro and in vivo. Mechanistically, serine metabolism deficiency increases the expression of IGF1 by reducing the promoter abundance of S-adenosyl methionine-dependent histone H3 lysine 27 trimethylation. IGF1 then activates the p38-dependent JAK-STAT1 axis to promote M(IFN-γ) polarization and suppress STAT6-mediated M(IL-4) activation. This study reveals a new mechanism by which serine metabolism orchestrates macrophage polarization and suggests the manipulation of serine metabolism as a therapeutic strategy for macrophage-mediated immune diseases.

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Serine Metabolism Orchestrates Macrophage Polarization by Regulating the IGF1–p38 Axis

Project description:Serine Metabolism Orchestrates Macrophage Polarization by Regulating the IGF1–p38 Axis

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Expression data of peritoneal macrophages from Wild-type mouse cultured in control or serine/glycine-depleted medium.

Project description:Activation of signaling pathways downstream of Toll-like receptor 4 upregulate expression of genes related to serine metabolism. We cultured peritoneal macrophages in control or serine/glycine-depleted medium for 24 hr, stimulated them with LPS (10 ng/ml) for 6 or 12 hr, and collected them to compare the gene expression. Microarray analysis revealed that serine/glycine-depletion in peritoneal macrophages upregulates gene expression of enzymes for serine biosynthesis.

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Exogenous and endogenous serine modulate polarization of tumor-associated macrophages to influence development of nasopharyngeal carcinoma

Project description:To investigate the global gene expression pattern in response to removal of exogenous serine/glycine from the medium, RNA-seq was performed using C666-1 cells cultured in CM or -SG medium for 24 h. The volcano plot exhibited 60 up-regulated and 123 down-regulated genes in C666-1 cells subjected to exogenous serine/glycine deprivation.

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Serine metabolism supports macrophage IL-1β production.

Project description:Serine is a substrate for nucleotides, NADPH and glutathione (GSH) synthesis. Previous studies in cancer cells and lymphocytes have shown that serine-dependent one-carbon units are necessary for nucleotide production to support proliferation. Presently, it is unknown whether serine metabolism impacts the function of non-proliferative cells, such as inflammatory macrophages. We find that in macrophages, serine is required for optimal lipopolysaccharide (LPS) induction of IL-1β mRNA expression, but not inflammasome activation. The mechanism involves a requirement for glycine, which is made from serine, to support macrophage glutathione (GSH) synthesis. Cell-permeable GSH, but not the one-carbon donor formate, rescues IL-1β mRNA expression. Pharmacological inhibition of de novo serine synthesis in vivo decreased LPS induction of IL-1β levels and improved survival in an LPS-driven model of sepsis in mice. Our study reveals that serine metabolism is necessary for GSH synthesis to support IL-1β cytokine production.

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Expression data from brain tissue of Rattus norvegicus treated with D-Serine

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RNA-seq on human muscle progenitor cells cultured with (1000 uM) or without serine and glycine

Project description:To determine the transcriptional response to serine and glycine deprivation in human muscle progenitor cells

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