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

Cellular & Molecular Immunology volume 19, pages 1263–1278 (2022)Cite this article

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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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Author notes

  1. These authors contributed equally: Xiao Shan, Penghui Hu, Lina Ni.

Authors and Affiliations

  1. Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Inflammation Biology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University; Division of Infectious Disease, Second Hospital of Tianjin Medical University, Tianjin, 300070, China

    Xiao Shan, Penghui Hu, Lina Ni, Long Shen, Yanan Zhang, Zemin Ji, Yan Cui & Qiujing Yu

  2. Institute for Genome Engineered Animal Models of Human Diseases, National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian, 116044, Liaoning, China

    Meihua Guo, Haoan Wang, Liyuan Ran & Yingjie Wu

  3. Shandong Provincial Hospital, School of Laboratory Animal and Shandong Laboratory Animal Center, Science and Technology Innovation Center, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250021, Shandong, China

    Liyuan Ran, Kun Yang & Yingjie Wu

  4. The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China

    Ting Wang

  5. Division of Infectious Disease, Second Hospital of Tianjin Medical University, Tianjin, 300070, China

    Lei Wang & Bin Chen

  6. Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China

    Zhi Yao

  7. Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY, 10010, USA

    Yingjie Wu

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  1. Xiao Shan
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Contributions

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.

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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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