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. Macrophage differentiation and inflammatory function are controlled by cell metabolism. Here, the authors use a viral hepatitis model and a high-fat diet model of insulin resistance to show how VSIG4 inhibits inflammatory macrophage activation by modulating mitochondrial pyruvate metabolism.
【초록키워드】 Inflammation, Macrophage, Pathogenesis, macrophages, obesity, metabolism, Protein, Hepatitis, mice, Viral hepatitis, insulin resistance, Phosphorylation, pathway, expression, murine hepatitis virus, macrophage activation, Inflammatory, regulate, mitochondrial, Exacerbation, Regulation, pyruvate, various inflammatory diseases, secretion, upregulation, cell metabolism, inflammatory function, susceptible, subsequent, inhibit, contribute, expressed, promote, activate, reduction in, reactive oxygen specy, Forced, modulating, PDK2, VSIG4, 【제목키워드】 metabolism, proinflammatory, macrophage activation, mitochondrial, pyruvate, inhibit, VSIG4,