Abstract
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.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
↵# equal contribution
1. Binding of Hif1α to the regulatory sequence of the ImpL2-RA transcriptional variant is demonstrated (Fig 1H). 2. Macrophage-derived ImpL2 suppresses insulin signaling in the fat body is demonstrated by tGPH reporter and rescue of ImpL2-induced effects by the foxo mutation demonstrates that the observed effects are mediated by Foxo (Fig 5). 3. Injecting flies with fluorescently labeled lipoproteins (LDL-pHRodo - Fig. 6E,F) demonstrates their uptake by macrophages. 4. All graphs are presented with individual values.
