Macrophage‐derived insulin antagonist ImpL2 induces lipoprotein mobilization upon bacterial infection

Abstract

The immune response is an energy‐demanding process that must be coordinated with systemic metabolic changes redirecting nutrients from stores to the immune system. Although this interplay is fundamental for the function of the immune system, the underlying mechanisms remain elusive. Our data show that the pro‐inflammatory polarization of Drosophila macrophages is coupled to the production of the insulin antagonist ImpL2 through the activity of the transcription factor HIF1α. ImpL2 production, reflecting nutritional demands of activated macrophages, subsequently impairs insulin signaling in the fat body, thereby triggering FOXO‐driven mobilization of lipoproteins. This metabolic adaptation is fundamental for the function of the immune system and an individual's resistance to infection. We demonstrated that analogically to Drosophila , mammalian immune‐activated macrophages produce ImpL2 homolog IGFBP7 in a HIF1α‐dependent manner and that enhanced IGFBP7 production by these cells induces mobilization of lipoproteins from hepatocytes. Hence, the production of ImpL2 /IGFBP7 by macrophages represents an evolutionarily conserved mechanism by which macrophages alleviate insulin signaling in the central metabolic organ to secure nutrients necessary for their function upon bacterial infection. image Organisms mount a successful immune response to infection by redirecting nutrients from their storage tissues to the immune system. Here, pro‐inflammatory macrophages are shown to produce insulin signaling antagonist ImpL2/IGFBP7, which invokes mobilization of lipoproteins for the immune response via silencing of insulin signaling in either Drosophila fat body or mammalian hepatocytes. Pro‐inflammatory macrophage polarization in Drosophila is coupled to IMPL2 production via HIF1α. IMPL2‐induced redistribution of lipids is essential for the survival of infection. IGFBP7 acts analogously to ImpL2 in mammalian liver. Macrophage‐induced silencing of insulin signaling is beneficial during bacterial infection.