VSIG4 inhibits proinflammatory macrophage activation by reprogramming mitochondrial pyruvate metabolism

Jialin Li, Bo Diao, Sheng Guo, Xiaoyong Huang, Chengying Yang, Zeqing Feng, Weiming Yan, Qin Ning, Lixin Zheng, Yongwen Chen () and Yuzhang Wu ()
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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

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-01327-4

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