Serine Metabolism Supports Macrophage IL-1? Production.

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-1? 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-1? mRNA expression. Pharmacological inhibition of de novo serine synthesis in vivo decreased LPS induction of IL-1? 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-1? cytokine production.

SUBMITTER: Rodriguez AE 

PROVIDER: S-EPMC6447453 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature