Serine metabolism orchestrates macrophage polarization by regulating the IGF1–p38 axis

Xiao Shan, Penghui Hu, Lina Ni, Long Shen, Yanan Zhang, Zemin Ji, Yan Cui, Meihua Guo, Haoan Wang, Liyuan Ran, Kun Yang, Ting Wang, Lei Wang, Bin Chen, Zhi Yao, Yingjie Wu, Qiujing Yu

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

Serine metabolism is reportedly involved in immune cell functions, but whether and how serine metabolism regulates macrophage polarization remain largely unknown. Here, we show that suppressing serine metabolism, either by inhibiting the activity of the key enzyme phosphoglycerate dehydrogenase in the serine biosynthesis pathway or by exogenous serine and glycine restriction, robustly enhances the polarization of interferon-γ-activated macrophages (M(IFN-γ)) but suppresses that of interleukin-4-activated macrophages (M(IL-4)) both in vitro and in vivo. Mechanistically, serine metabolism deficiency increases the expression of IGF1 by reducing the promoter abundance of S-adenosyl methionine-dependent histone H3 lysine 27 trimethylation. IGF1 then activates the p38-dependent JAK–STAT1 axis to promote M(IFN-γ) polarization and suppress STAT6-mediated M(IL-4) activation. This study reveals a new mechanism by which serine metabolism orchestrates macrophage polarization and suggests the manipulation of serine metabolism as a therapeutic strategy for macrophage-mediated immune diseases.

Original languageEnglish
Pages (from-to)1263-1278
Number of pages16
JournalCellular and Molecular Immunology
Volume19
Issue number11
DOIs
StatePublished - Nov 2022
Externally publishedYes

Keywords

  • IGF1
  • Macrophage polarization
  • PHGDH
  • SAM
  • Serine metabolism
  • p38

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