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Lipid synthesis, triggered by PPARγ T166 dephosphorylation, sustains reparative function of macrophages during tissue repair

Author

Listed:
  • Shiman Zuo

    (Nanjing University)

  • Yuxin Wang

    (Nanjing University)

  • Hanjing Bao

    (Nanjing University)

  • Zehui Zhang

    (Nanjing University)

  • Nanfei Yang

    (Nanjing University)

  • Meng Jia

    (Nanjing University)

  • Qing Zhang

    (Nanjing University)

  • Ani Jian

    (Nanjing University)

  • Rong Ji

    (Nanjing University)

  • Lidan Zhang

    (Nanjing University)

  • Yan Lu

    (Nanjing University)

  • Yahong Huang

    (Nanjing University)

  • Pingping Shen

    (Nanjing University
    Shenzhen Research Institute of Nanjing University)

Abstract

Macrophages may acquire a reparative phenotype that supports tissue repair and remodeling in response to tissue injury. However, the metabolic requirements underpinning this process are incompletely understood. Here, we show that posttranslational modification (PTM) of PPARγ regulates lipid synthesis in response to wound microenvironmental cues and that metabolic rewiring orchestrates function of reparative macrophages. In injured tissues, repair signaling leads to decreased macrophage PPARγ threonine 166 (T166) phosphorylation, which results in a partially active PPARγ transcriptional program comprised of increased binding activity to the regulator regions of lipid synthesis-associated genes, thereby increased lipogenesis. The accumulated lipids serve as signaling molecules, triggering STAT3-mediated growth factor expression, and supporting the synthesis of phospholipids for the expansion of the endoplasmic reticulum (ER), which is required for protein secretion. Genetic or pharmacological inhibition of PPARγ T166 phosphorylation promotes the reparative function of macrophages and facilitates tissue regeneration. In summary, our work identifies PPARγ T166-regulated lipid biosynthesis as an essential pathway for meeting the anabolic demands of the activation and function of macrophages and provides a rationale for potential therapeutic targeting of tissue repair.

Suggested Citation

  • Shiman Zuo & Yuxin Wang & Hanjing Bao & Zehui Zhang & Nanfei Yang & Meng Jia & Qing Zhang & Ani Jian & Rong Ji & Lidan Zhang & Yan Lu & Yahong Huang & Pingping Shen, 2024. "Lipid synthesis, triggered by PPARγ T166 dephosphorylation, sustains reparative function of macrophages during tissue repair," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51736-5
    DOI: 10.1038/s41467-024-51736-5
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