Macrophage-derived insulin/IGF antagonist ImpL2 regulates systemic metabolism for mounting an effective acute immune response inDrosophila

Abstract

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.

Macrophages and Their Organ Locations Shape Each Other in Development and Homeostasis – A Drosophila Perspective

“…In response to bacterial infection, hemocytes communicate to the fat body through signals including Upd3 and the Toll ligand Spätzle to induce AMP expression, in both the larva and adult ( Agaisse et al, 2003 ; Brennan et al, 2007 ; Charroux and Royet, 2009 ; Shia et al, 2009 ; Honti et al, 2014 ; Sanchez Bosch et al, 2019 ). Bacterial infection also stimulates hemocytes to release ImpL2, an insulin/IGF antagonist, which induces the release of lipoproteins and carbohydrates from the fat body to fuel the immune response ( Gabriela et al, 2020 ); in turn, hemocytes switch to aerobic glycolysis, which supports the antibacterial defense ( Krejèová et al, 2019 ).…”

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

“…JAK/STAT signaling directly induces the expression of Ecdysone-inducible gene L2 (ImpL2), an insulin binding protein (Terry et al, 2006;Amoyel et al, 2016). We illustrate that, as is the case with adult Drosophila, ImpL2 plays an important role in the cross talk between immune cells and the periphery, in terms of nutrient distribution during immune response (preprint: Krejčová et al, 2021). In the case of this manuscript, we focus on the communication that takes place between muscle tissue and the immune system.…”

“…According to the concept of selfish immunity, resources can be redirected to the immune system by inducing insulin resistance in non-immune tissues (Straub, 2014). Insulin resistance is predominantly studied in a pathological context (Gurzov et al, 2016;Lourido et al, 2021) and its adaptive function during the acute immune response is largely unexplored (preprint: Krejčová et al, 2021).…”

The reproductive status determines tolerance and resistance to Mycobacterium marinum in Drosophila melanogaster

“…This fact has been recently described as the ‘selfish immune system theory’, which is based on the fact that activated phagocytes release signalling molecules (selfish immune factors, SIFs) that regulate host energy to steal resources from other non-immune tissues [ 24–27 ]. Authors propose the insulin/insulin-like growth factor (IGF) antagonist Imaginal morphogenesis protein late 2 (Impl2)—which has been identified as a cancer-derived cachectic factor in flies—and Upd3 as potential SIFs in Drosophila [ 28–30 ].…”