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 Chandel*

*Corresponding author for this work

Research output: Contribution to journalArticle

1 Citation (Scopus)

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

Fingerprint

Interleukin-1
Serine
Macrophages
Lipopolysaccharides
formic acid
Carbon
Nucleotides
Inflammasomes
Messenger RNA
NADP
Glycine
Glutathione
Sepsis
Pharmacology
Lymphocytes
Cytokines
Neoplasms

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

Cite this

Rodriguez, A. E., Ducker, G. S., Billingham, L. K., Martinez, C. A., Mainolfi, N., Suri, V., ... Chandel, N. (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
Rodriguez, Arianne E. ; Ducker, Gregory S. ; Billingham, Leah K. ; Martinez, Carlos A. ; Mainolfi, Nello ; Suri, Vipin ; Friedman, Adam ; Manfredi, Mark G. ; Weinberg, Samuel E. ; Rabinowitz, Joshua D. ; Chandel, Navdeep. / Serine Metabolism Supports Macrophage IL-1β Production. In: Cell Metabolism. 2019 ; Vol. 29, No. 4. pp. 1003-1011.e4.
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Rodriguez, AE, Ducker, GS, Billingham, LK, Martinez, CA, Mainolfi, N, Suri, V, Friedman, A, Manfredi, MG, Weinberg, SE, Rabinowitz, JD & Chandel, N 2019, 'Serine Metabolism Supports Macrophage IL-1β Production', Cell Metabolism, vol. 29, no. 4, pp. 1003-1011.e4. https://doi.org/10.1016/j.cmet.2019.01.014

Serine Metabolism Supports Macrophage IL-1β Production. / Rodriguez, Arianne E.; Ducker, Gregory S.; Billingham, Leah K.; Martinez, Carlos A.; Mainolfi, Nello; Suri, Vipin; Friedman, Adam; Manfredi, Mark G.; Weinberg, Samuel E.; Rabinowitz, Joshua D.; Chandel, Navdeep.

In: Cell Metabolism, Vol. 29, No. 4, 02.04.2019, p. 1003-1011.e4.

Research output: Contribution to journalArticle

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T1 - Serine Metabolism Supports Macrophage IL-1β Production

AU - Rodriguez, Arianne E.

AU - Ducker, Gregory S.

AU - Billingham, Leah K.

AU - Martinez, Carlos A.

AU - Mainolfi, Nello

AU - Suri, Vipin

AU - Friedman, Adam

AU - Manfredi, Mark G.

AU - Weinberg, Samuel E.

AU - Rabinowitz, Joshua D.

AU - Chandel, Navdeep

PY - 2019/4/2

Y1 - 2019/4/2

N2 - 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.

AB - 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.

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Rodriguez AE, Ducker GS, Billingham LK, Martinez CA, Mainolfi N, Suri V et al. Serine Metabolism Supports Macrophage IL-1β Production. Cell Metabolism. 2019 Apr 2;29(4):1003-1011.e4. https://doi.org/10.1016/j.cmet.2019.01.014