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.
Original language | English (US) |
---|---|
Pages (from-to) | 1003-1011.e4 |
Journal | Cell Metabolism |
Volume | 29 |
Issue number | 4 |
DOIs | |
State | Published - Apr 2 2019 |
All Science Journal Classification (ASJC) codes
- Physiology
- Molecular Biology
- Cell Biology
Keywords
- IL-1beta
- LPS response
- glutathione
- immunometabolism
- inflammation
- macrophage
- one-carbon metabolism
- sepsis
- serine metabolism