- 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 HIF1 alpha. 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 HIF1 alpha-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. AD - Univ South Bohemia, Fac Sci, Dept Mol Biol & Genet, Ceske Budejovice, Czech Republic AD - Karolinska Inst, Integrated Cardio Metab Ctr ICMC, Dept Med, Huddinge, Sweden AD - Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany AD - Univ Tubingen, Tubingen, Germany AD - Biol Ctr CAS, Inst Parasitol, Ceske Budejovice, Czech Republic AD - Univ South Bohemia, Fac Sci, Dept Expt Plant Biol, Ceske Budejovice, Czech Republic AD - Univ Oregon, Inst Mol Biol, Oregon City, OR USA AD - Biol Ctr CAS, Inst Entomol, Ceske Budejovice, Czech Republic
Macrophage-derived insulin antagonist ImpL2 induces lipoprotein mobilization upon bacterial infection T2
Morgantini C;
2023-01-01
Abstract
- 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 HIF1 alpha. 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 HIF1 alpha-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. AD - Univ South Bohemia, Fac Sci, Dept Mol Biol & Genet, Ceske Budejovice, Czech Republic AD - Karolinska Inst, Integrated Cardio Metab Ctr ICMC, Dept Med, Huddinge, Sweden AD - Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany AD - Univ Tubingen, Tubingen, Germany AD - Biol Ctr CAS, Inst Parasitol, Ceske Budejovice, Czech Republic AD - Univ South Bohemia, Fac Sci, Dept Expt Plant Biol, Ceske Budejovice, Czech Republic AD - Univ Oregon, Inst Mol Biol, Oregon City, OR USA AD - Biol Ctr CAS, Inst Entomol, Ceske Budejovice, Czech RepublicI documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
