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

doi:10.1016/j.cmet.2019.01.014

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 journal › Article

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 language	English (US)
Pages (from-to)	1003-1011.e4
Journal	Cell Metabolism
Volume	29
Issue number	4
DOIs	https://doi.org/10.1016/j.cmet.2019.01.014
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

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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

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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.",

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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 S.

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

Research output: Contribution to journal › Article

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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 S.

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