2. Academic Validation
  3. Serine metabolism orchestrates macrophage polarization by regulating the IGF1-p38 axis

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

  • Cell Mol Immunol. 2022 Nov;19(11):1263-1278. doi: 10.1038/s41423-022-00925-7.
Xiao Shan # 1,  Penghui Hu # 1,  Lina Ni # 1,  Long Shen 1,  Yanan Zhang 1,  Zemin Ji 1,  Yan Cui 1,  Meihua Guo 2,  Haoan Wang 2,  Liyuan Ran 2 3,  Kun Yang 3,  Ting Wang 4,  Lei Wang 5,  Bin Chen 5,  Zhi Yao 6,  Yingjie Wu 7 8 9,  Qiujing Yu 10
Affiliations

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.
  • 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.
  • 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.
  • 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.
  • 5 Division of Infectious Disease, Second Hospital of Tianjin Medical University, Tianjin, 300070, China.
  • 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. [email protected].
  • 7 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. [email protected].
  • 8 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. [email protected].
  • 9 Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY, 10010, USA. [email protected].
  • 10 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. [email protected].
  • # Contributed equally.
PMID: 36180780 DOI: 10.1038/s41423-022-00925-7
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.

Keywords

IGF1; Macrophage polarization; PHGDH; SAM; Serine metabolism; p38.

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