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
  • 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: [email protected].
  • 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: [email protected].
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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