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

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.

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Acknowledgements

We thank Dr. Xiaoyue Tan (Nankai University, China) for kindly providing the Lyz2-Cre mice and several cell lines. This research was supported by grants from the Tianjin Municipal Natural Science Foundation of China (20JCYBJC00220, QY) and from the National Natural Science Foundation of China: 81672710 (QY), 81872239 (QY), 82073051 (TW), 81874055 (TW), and 81902900 (LS).

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QY conceived the project and designed the experiments. QY, YW, and ZY wrote and edited the manuscript. TW, LW, and BC helped with editing the manuscript. XS, PH, LN, LS, YZ, ZJ, and YC conducted the experiments. MG, HW, LR, and KY contributed the IGF1Rfl/fl mice.

Corresponding authors

Correspondence to Zhi Yao, Yingjie Wu or Qiujing Yu.

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Shan, X., Hu, P., Ni, L. et al. Serine metabolism orchestrates macrophage polarization by regulating the IGF1–p38 axis. Cell Mol Immunol 19, 1263–1278 (2022). https://doi.org/10.1038/s41423-022-00925-7

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  • DOI: https://doi.org/10.1038/s41423-022-00925-7

Keywords

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

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