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VSIG4 inhibits proinflammatory macrophage activation by reprogramming mitochondrial pyruvate metabolism

Author

Listed:
  • Jialin Li

    (Third Military Medical University)

  • Bo Diao

    (Third Military Medical University)

  • Sheng Guo

    (Third Military Medical University)

  • Xiaoyong Huang

    (Third Military Medical University)

  • Chengying Yang

    (Third Military Medical University)

  • Zeqing Feng

    (Third Military Medical University)

  • Weiming Yan

    (Huazhong University of Science and Technology)

  • Qin Ning

    (Huazhong University of Science and Technology)

  • Lixin Zheng

    (National Institute of Allergy and Infectious Diseases)

  • Yongwen Chen

    (Third Military Medical University)

  • Yuzhang Wu

    (Third Military Medical University)

Abstract

Exacerbation of macrophage-mediated inflammation contributes to pathogenesis of various inflammatory diseases, but the immunometabolic programs underlying regulation of macrophage activation are unclear. Here we show that V-set immunoglobulin-domain-containing 4 (VSIG4), a B7 family-related protein that is expressed by resting macrophages, inhibits macrophage activation in response to lipopolysaccharide. Vsig4 −/− mice are susceptible to high-fat diet-caused obesity and murine hepatitis virus strain-3 (MHV-3)-induced fulminant hepatitis due to excessive macrophage-dependent inflammation. VSIG4 activates the PI3K/Akt–STAT3 pathway, leading to pyruvate dehydrogenase kinase-2 (PDK2) upregulation and subsequent phosphorylation of pyruvate dehydrogenase, which results in reduction in pyruvate/acetyl-CoA conversion, mitochondrial reactive oxygen species secretion, and macrophage inhibition. Conversely, interruption of Vsig4 or Pdk2 promotes inflammation. Forced expression of Vsig4 in mice ameliorates MHV-3-induced viral fulminant hepatitis. These data show that VSIG4 negatively regulates macrophage activation by reprogramming mitochondrial pyruvate metabolism.

Suggested Citation

  • Jialin Li & Bo Diao & Sheng Guo & Xiaoyong Huang & Chengying Yang & Zeqing Feng & Weiming Yan & Qin Ning & Lixin Zheng & Yongwen Chen & Yuzhang Wu, 2017. "VSIG4 inhibits proinflammatory macrophage activation by reprogramming mitochondrial pyruvate metabolism," Nature Communications, Nature, vol. 8(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01327-4
    DOI: 10.1038/s41467-017-01327-4
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    Cited by:

    1. Guihong Lu & Xiaojun Wang & Feng Li & Shuang Wang & Jiawei Zhao & Jinyi Wang & Jing Liu & Chengliang Lyu & Peng Ye & Hui Tan & Weiping Li & Guanghui Ma & Wei Wei, 2022. "Engineered biomimetic nanoparticles achieve targeted delivery and efficient metabolism-based synergistic therapy against glioblastoma," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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