Macrophage-derived insulin/IGF antagonist ImpL2 regulates systemic metabolism for mounting an effective acute immune response in Drosophila

In response to invading pathogens, macrophages metabolically polarize toward Hif1α-induced aerobic glycolysis, requiring increased supply of nutrients. Here, we show that in order to obtain sufficient resources, Drosophila macrophages release the insulin/IGF antagonist ImpL2 in a Hif1α-dependent manner as a reflection of adopted polarization. ImpL2 remotely induces Foxo-mediated lipid mobilization and the release of lipoproteins and carbohydrates from adipose tissue to be utilized by the activated immune system. Although these ImpL2 effects are essential in acute streptococcal infection, they become maladaptive during chronic intracellular Listeria infection. The relevance of our model to mammalian immuno-metabolism is documented by the increased expression of the ImpL2 homolog IGFBP7 in human macrophages exposed to Streptococcus. Therefore, we postulate that ImpL2/IGFBP7 induce resource mobilization, which is beneficial during the acute phase of infection but may act as cachectic factors in patients with cancer, sepsis, or obesity.