VSIG4 inhibits proinflammatory macrophage activation by reprogramming mitochondrial pyruvate metabolism

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.

Single-cell analysis of Crohn’s disease lesions identifies a pathogenic cellular module associated with resistance to anti-TNF therapy

“…The gut tissue-resident macrophage subset expressed high levels of the macrophage transcription factors (TF) MAFB and M-CSF receptor ( CSF1R ) (Lavin et al, 2014), genes required for the clearance of cellular debris ( DNASE1L3 and complement 1q genes C1QA , C1QB , C1QC ) (Sisirak et al, 2016), immune modulation (e.g. the B7 family related-member VSIG4 ), and resolution of inflammation ( MRC1 ) (Lee et al, 2002; Li et al, 2017) ( Figure 2B ). Further analysis showed the restricted expression of several genes like FOLR2 , FUCA1 , GPNMB and LILRB5 to one of the two clusters of gut tissue-resident macrophage, possibly indicative of different metabolic states and/or niche within the ileum.…”

Reduction and Functional Exhaustion of T Cells in Patients with Coronavirus Disease 2019 (COVID-19)

“…However, the cytokine storm in turn may promote apoptosis or necrosis of T cells, and consequently leads to their reduction. Our previous work demonstrating that monocytes and macrophages can produce pro-inflammatory cytokine during murine hepatitis virus strain-3 infection, 30,31 and whether SARS-CoV-2 also triggers cytokine release from monocytes and macrophages in COVID-19 patients need further investigation and such work is in progress in our hospital.…”

Human genetic basis of fulminant viral hepatitis

“…A few KO mice have been tested, some of which were more susceptible than WT mice, with earlier and higher mortality. These models included knockouts of programmed death (PD)-1, IL-33 and V-set immunoglobulin domain-containing 4 (VSIG4) (Carriere et al 2017;Chen et al 2011;Li et al 2017). PD-1 modulates the balance between the antimicrobial immune response and immune system-mediated tissue damage.…”

“…It is expressed exclusively in tissue macrophages, including Kupffer cells. Inflammatory cytokines, not only such as IFNγ and TNFγ but also FGL2, are strongly induced in VSIG4-KO mice, leading to uncontrolled macrophage-mediated inflammation and tissue damage (Li et al 2017).…”