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Li J
; Diao B
; Guo S
; Huang X
; Yang C
; Feng Z
; Yan W
; Ning Q
; Zheng L
; Chen Y
; Wu Y
Nat Commun
2017[Nov]; 8
(1
): 1322
PMID29109438
show ga
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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