2. Academic Validation
  3. VSIG4 inhibits proinflammatory macrophage activation by reprogramming mitochondrial pyruvate metabolism

VSIG4 inhibits proinflammatory macrophage activation by reprogramming mitochondrial pyruvate metabolism

  • Nat Commun. 2017 Nov 6;8(1):1322. doi: 10.1038/s41467-017-01327-4.
Jialin Li 1,  Bo Diao 1,  Sheng Guo 1,  Xiaoyong Huang 1,  Chengying Yang 1,  Zeqing Feng 1,  Weiming Yan 2,  Qin Ning 2,  Lixin Zheng 3,  Yongwen Chen 4,  Yuzhang Wu 5
Affiliations

Affiliations

  • 1 Institute of Immunology, PLA, Third Military Medical University, Chongqing, 400038, China.
  • 2 Institute of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
  • 3 Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, MD, 20892, USA.
  • 4 Institute of Immunology, PLA, Third Military Medical University, Chongqing, 400038, China. yongwench@163.com.
  • 5 Institute of Immunology, PLA, Third Military Medical University, Chongqing, 400038, China. wuyuzhang@tmmu.edu.cn.
PMID: 29109438 DOI: 10.1038/s41467-017-01327-4
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.

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