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 › peer-review

34 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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@article{d63c5429ae8c4708892a9089bf3db516,

title = "Serine Metabolism Supports Macrophage IL-1β 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-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.",

keywords = "IL-1beta, LPS response, glutathione, immunometabolism, inflammation, macrophage, one-carbon metabolism, sepsis, serine metabolism",

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

note = "Funding Information: This work was supported by the NIH to N.S.C. ( 5P01AG049665 , 5P01HL071643 , and 5T32HL076139-15 ) and J.D.R. ( 5DP1DK113643-03 ), with support from the Ford Foundation to A.E.R. G.S.D. is supported by a fellowship from the NCI ( K99 CA215307 ). Flow cytometric analysis was supported by the Northwestern University Flow Cytometry Core Facility supported by Cancer Center Support Grant ( NCI CA060553 ). Flow cytometry cell sorting was performed on a BD FACSAria SORP system, purchased through the support of NIH 1S10OD011996-01 . We would like to thank Hiam Abdala-Valencia and Kiwon Nam for RNA sequencing. We thank Peng Gao in the metabolomics core within the Robert Lurie Comprehensive Cancer Center for metabolomics analysis. ",

year = "2019",

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doi = "10.1016/j.cmet.2019.01.014",

language = "English (US)",

volume = "29",

pages = "1003--1011.e4",

journal = "Cell Metabolism",

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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 › peer-review

TY - JOUR

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 S.

N1 - Funding Information: This work was supported by the NIH to N.S.C. ( 5P01AG049665 , 5P01HL071643 , and 5T32HL076139-15 ) and J.D.R. ( 5DP1DK113643-03 ), with support from the Ford Foundation to A.E.R. G.S.D. is supported by a fellowship from the NCI ( K99 CA215307 ). Flow cytometric analysis was supported by the Northwestern University Flow Cytometry Core Facility supported by Cancer Center Support Grant ( NCI CA060553 ). Flow cytometry cell sorting was performed on a BD FACSAria SORP system, purchased through the support of NIH 1S10OD011996-01 . We would like to thank Hiam Abdala-Valencia and Kiwon Nam for RNA sequencing. We thank Peng Gao in the metabolomics core within the Robert Lurie Comprehensive Cancer Center for metabolomics analysis.

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.

KW - IL-1beta

KW - LPS response

KW - glutathione

KW - immunometabolism

KW - inflammation

KW - macrophage

KW - one-carbon metabolism

KW - sepsis

KW - serine metabolism

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DO - 10.1016/j.cmet.2019.01.014

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SP - 1003-1011.e4

JO - Cell Metabolism

JF - Cell Metabolism

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