2. Academic Validation
  3. One-Carbon Metabolism Supports S-Adenosylmethionine and Histone Methylation to Drive Inflammatory Macrophages

One-Carbon Metabolism Supports S-Adenosylmethionine and Histone Methylation to Drive Inflammatory Macrophages

  • Mol Cell. 2019 Sep 19;75(6):1147-1160.e5. doi: 10.1016/j.molcel.2019.06.039.
Weiwei Yu 1,  Zhen Wang 2,  Kailian Zhang 2,  Zhexu Chi 2,  Ting Xu 2,  Danlu Jiang 2,  Sheng Chen 2,  Wenxin Li 1,  Xuyan Yang 3,  Xue Zhang 4,  Yingliang Wu 5,  Di Wang 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China.
  • 2 Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China.
  • 3 Department of Rheumatology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
  • 4 Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou 310058, China.
  • 5 State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China. Electronic address: ylwu@whu.edu.cn.
  • 6 Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China; Department of Orthopedic Surgery of the Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China. Electronic address: diwang@zju.edu.cn.
PMID: 31420217 DOI: 10.1016/j.molcel.2019.06.039
Abstract

Activated macrophages adapt their metabolic pathways to drive the pro-inflammatory phenotype, but little is known about the biochemical underpinnings of this process. Here, we find that lipopolysaccharide (LPS) activates the pentose phosphate pathway, the serine synthesis pathway, and one-carbon metabolism, the synergism of which drives epigenetic reprogramming for interleukin-1β (IL-1β) expression. Glucose-derived ribose and one-carbon units fed by both glucose and serine metabolism are synergistically integrated into the methionine cycle through de novo ATP synthesis and fuel the generation of S-adenosylmethionine (SAM) during LPS-induced inflammation. Impairment of these metabolic pathways that feed SAM generation lead to anti-inflammatory outcomes, implicating SAM as an essential metabolite for inflammatory macrophages. Mechanistically, SAM generation maintains a relatively high SAM:S-adenosylhomocysteine ratio to support histone H3 lysine 36 trimethylation for IL-1β production. We therefore identify a synergistic effect of glucose and amino acid metabolism on orchestrating SAM availability that is intimately linked to the chromatin state for inflammation.

Keywords

H3K36me3; S-adenosylmethionine; amino-acid metabolism; epigenetic reprogramming; glycolysis offshoots; inflammation; one-carbon metabolism.

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