Mechanism of lipid droplet accumulation in mononuclear phagocytes during sepsis

Lipid droplet formation in phagocytes is associated with various important inflammatory conditions, and their accumulation modulates disease progression. We used proteomics, lipidomics, and cell bioenergetics experiments to unravel the metabolic basis of lipid droplet accumulation in a murine model of Salmonella infection. Lipid droplets accumulated in inflammatory monocytes and neutrophils within spleen inflammatory lesions, and this is recapitulated in vitro by treating monocytes with the pro-inflammatory cytokine IFNγ. Bioenergetic experiments suggested that iNOS-derived nitric oxide blocks the mitochondrial electron transport chain thus inhibiting respiration and oxidation of fatty acids, which instead accumulate within lipid droplets. Surprisingly, metabolite tracing with 13 C-labeled substrates revealed that de novo synthesis of fatty acid from glutamine or glucose plays no major role in lipid accumulation, in stark contrast to the otherwise similar metabolism of cancer cells. Instead, the glycerol head group in triacylglycerol and phospholipid entirely derives from glucose, while the fatty acid carbons originate from uptake of external lipids. Our results identify neutrophils and inflammatory monocytes as a depot of neutral lipid during infection, and establish remodeling of imported lipids with exchange of head groups for newly synthesized glycerol as the underlying metabolic mechanism of lipid droplet accumulation upon activation with IFNγ.