Serine Metabolism Supports Macrophage IL-1β Production.

TitleSerine Metabolism Supports Macrophage IL-1β Production.
Publication TypeJournal Article
Year of Publication2019
AuthorsRodriguez, AE, Ducker, GS, Billingham, LK, Martinez, CA, Mainolfi, N, Suri, V, Friedman, A, Manfredi, MG, Weinberg, SE, Rabinowitz, JD, Chandel, NS
JournalCell Metab
Volume29
Issue4
Pagination1003-1011.e4
Date Published2019 Apr 02
ISSN1932-7420
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.

DOI10.1016/j.cmet.2019.01.014
Alternate JournalCell Metab.
PubMed ID30773464
PubMed Central IDPMC6447453
Grant ListDP1 DK113643 / DK / NIDDK NIH HHS / United States
P01 AG049665 / AG / NIA NIH HHS / United States
P01 HL071643 / HL / NHLBI NIH HHS / United States
K99 CA215307 / CA / NCI NIH HHS / United States
P30 CA060553 / CA / NCI NIH HHS / United States
T32 HL076139 / HL / NHLBI NIH HHS / United States