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Cell Metab. 2019 Apr 2;29(4):1003-1011.e4. doi: 10.1016/j.cmet.2019.01.014. Epub 2019 Feb 14.

Serine Metabolism Supports Macrophage IL-1β Production.

Author information

1
Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
2
Lewis-Sigler Institute for Integrative Genomics and Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.
3
Raze Therapeutics, Cambridge, MA 02139, USA.
4
Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. Electronic address: nav@northwestern.edu.

Abstract

Serine is a substrate for nucleotide, 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 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.

KEYWORDS:

IL-1beta; LPS response; glutathione; immunometabolism; inflammation; macrophage; one-carbon metabolism; sepsis; serine metabolism

PMID:
30773464
PMCID:
PMC6447453
[Available on 2020-04-02]
DOI:
10.1016/j.cmet.2019.01.014

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