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.

中文翻译：

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巨噬细胞源性胰岛素拮抗剂 ImpL2 在细菌感染时诱导脂蛋白动员

免疫反应是一个需要能量的过程，必须与将营养物质从储存转移到免疫系统的全身代谢变化相协调。尽管这种相互作用对于免疫系统的功能至关重要，但其潜在机制仍然难以捉摸。我们的数据表明，果蝇巨噬细胞的促炎极化通过转录因子 HIF1α 的活性与胰岛素拮抗剂ImpL2的产生耦合。ImpL2的产生反映了活化巨噬细胞的营养需求，随后损害脂肪体内的胰岛素信号传导，从而触发 FOXO 驱动的脂蛋白动员。这种代谢适应对于免疫系统的功能和个体对感染的抵抗力至关重要。我们证明，与果蝇类似，哺乳动物免疫激活的巨噬细胞以 HIF1α 依赖性方式产生ImpL2同源物 IGFBP7，并且这些细胞增强的 IGFBP7 产生诱导肝细胞中脂蛋白的动员。因此，巨噬细胞产生ImpL2 /IGFBP7代表了一种进化上保守的机制，巨噬细胞通过该机制减轻中央代谢器官中的胰岛素信号传导，以确保其在细菌感染时发挥功能所需的营养。