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Serine metabolism supports macrophage IL-1beta production.

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Some of the oldest drugs targeting metabolism are the antifolates such as aminopterin and methotrexate (MTX). MTX started being used in the 1950s to treat rheumatoid arthritis. Aminopterin and MTX both target one carbon metabolism and inhibit proliferation of cells. MTX was a potent inhibitor of inflammation, because it prevented immune cell proliferation. One of the most important components of one carbon metabolism is serine. Serine, through one carbon metabolism, is a substrate for nucleotides, NADPH and glutathione (GSH) synthesis. Previous studies in cancer cells and lymphocytes have shown that serine-dependent one-carbon units are specifically 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 have found that serine is required for early inflammatory responses in macrophages. We demonstrate specifically that 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 glutathione (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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