@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. Experimental design and execution were conducted by A.E.R. G.S.D. L.K.B. S.E.W. J.D.R. and N.S.C. The PHGDH inhibitor was developed by N.M. V.S. A.F. and M.G.M. Data interpretation was performed by A.E.R. G.S.D. J.D.R. and N.S.C. Bioinformatics analysis was conducted by C.A.M. The manuscript was written and edited by A.E.R. G.S.D. J.D.R. and N.S.C. A.E.R. L.K.B. S.E.W. and N.S.C. have nothing to declare. J.D.R. is a founder of Raze Therapeutics and Princeton University and has filed patents for inventions of J.D.R. and G.S.D. related to one-carbon metabolism. N.M. V.S. A.F. and M.G.M. are employees of Raze Therapeutics. M.G.M. is a consultant and shareholder of Raze Therapeutics. A.F. is a founder, consultant, and shareholder of Raze Therapeutics. N.M. is a consultant and shareholder of Raze Therapeutics. V.S. is a consultant and shareholder of Raze Therapeutics. N.M. is an inventor on applications WO2017156165A1, WO2017023894A1, WO2017156181A1, and WO2017156177A1 pertaining to PHGDH inhibitors and their uses. 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. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2019",
month = apr,
day = "2",
doi = "10.1016/j.cmet.2019.01.014",
language = "English (US)",
volume = "29",
pages = "1003--1011.e4",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "4",
}