Serine Metabolism Supports Macrophage IL-1β Production

Arianne E. Rodriguez, Gregory S. Ducker, Leah K. Billingham, Carlos A. Martinez, Nello Mainolfi, Vipin Suri, Adam Friedman, Mark G. Manfredi, Samuel E. Weinberg, Joshua D. Rabinowitz, Navdeep S. Chandel

Research output: Contribution to journalArticle

22 Scopus citations

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 languageEnglish (US)
Pages (from-to)1003-1011.e4
JournalCell Metabolism
Volume29
Issue number4
DOIs
StatePublished - 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

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    Rodriguez, A. E., Ducker, G. S., Billingham, L. K., Martinez, C. A., Mainolfi, N., Suri, V., Friedman, A., Manfredi, M. G., Weinberg, S. E., Rabinowitz, J. D., & Chandel, N. S. (2019). Serine Metabolism Supports Macrophage IL-1β Production. Cell Metabolism, 29(4), 1003-1011.e4. https://doi.org/10.1016/j.cmet.2019.01.014