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

In response to invading pathogens, macrophages metabolically polarize towards 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, whose expression is regulated by Hif1α. ImpL2 remotely induces the release of lipids and carbohydrates from adipose tissue by reducing insulin signaling, followed by increased nutrient accumulation in activated immune cells. ImpL2 thus translates the metabolic requirements of immune cells into a systemic metabolic switch. Although these ImpL2 effects are essential during the acute immune response to streptococcal infection, they become maladaptive upon chronic infection by an intracellular pathogen. The relevance of our model to mammalian immunometabolism is demonstrated by the increased expression of the ImpL2 homolog IGFBP7 in human macrophages exposed to Streptococcus.