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.

Biology Centre CAS Institute of Parasitology Ceske Budejovice Czech Republic

Department of Experimental Plant Biology Faculty of Science University of South Bohemia Ceske Budejovice Czech Republic

Department of Medicine Integrated Cardio Metabolic Center Karolinska Institutet Huddinge Sweden

Department of Molecular Biology and Genetics Faculty of Science University of South Bohemia Ceske Budejovice Czech Republic

Dr Margarete Fischer Bosch Institute of Clinical Pharmacology Stuttgart Germany

Institute of Entomology Biology Centre CAS Ceske Budejovice Czech Republic

Institute of Molecular Biology University of Oregon Oregon City OR USA

University of Tübingen Tübingen Germany

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JAK/STAT mediated insulin resistance in muscles is essential for effective immune response

How to eliminate pathogen without killing oneself? Immunometabolism of encapsulation and melanization in Drosophila

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