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Macrophage-mediated phagocytosis and cytokine production represent the front lines of resistance to bacterial invaders. A key feature of this pro-inflammatory response in mammals is the complex remodeling of cellular metabolism towards aerobic glycolysis. Although the function of bactericidal macrophages is highly conserved, the metabolic remodeling of insect macrophages remains poorly understood. Here, we used adults of the fruit fly Drosophila melanogaster to investigate the metabolic changes that occur in macrophages during the acute and resolution phases of Streptococcus-induced sepsis. Our studies revealed that orthologs of Hypoxia inducible factor 1α (HIF1α) and Lactate dehydrogenase (LDH) are required for macrophage activation, their bactericidal function, and resistance to infection, thus documenting the conservation of this cellular response between insects and mammals. Further, we show that macrophages employing aerobic glycolysis induce changes in systemic metabolism that are necessary to meet the biosynthetic and energetic demands of their function and resistance to bacterial infection.

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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.