Polarization of Macrophages in Insects: Opening Gates for Immuno-Metabolic Research

Abstract

Insulin resistance and cachexia represent severe metabolic syndromes accompanying a variety of human pathological states, from life-threatening cancer and sepsis to chronic inflammatory states, such as obesity and autoimmune disorders. Although the origin of these metabolic syndromes has not been fully comprehended yet, a growing body of evidence indicates their possible interconnection with the acute and chronic activation of an innate immune response. Current progress in insect immuno-metabolic research reveals that the induction of insulin resistance might represent an adaptive mechanism during the acute phase of bacterial infection. In Drosophila, insulin resistance is induced by signaling factors released by bactericidal macrophages as a reflection of their metabolic polarization toward aerobic glycolysis. Such metabolic adaptation enables them to combat the invading pathogens efficiently but also makes them highly nutritionally demanding. Therefore, systemic metabolism has to be adjusted upon macrophage activation to provide them with nutrients and thus support the immune function. That anticipates the involvement of macrophage-derived systemic factors mediating the inter-organ signaling between macrophages and central energy-storing organs. Although it is crucial to coordinate the macrophage cellular metabolism with systemic metabolic changes during the acute phase of bacterial infection, the action of macrophage-derived factors may become maladaptive if chronic or in case of infection by an intracellular pathogen. We hypothesize that insulin resistance evoked by macrophage-derived signaling factors represents an adaptive mechanism for the mobilization of sources and their preferential delivery toward the activated immune system. We consider here the validity of the presented model for mammals and human medicine. The adoption of aerobic glycolysis by bactericidal macrophages as well as the induction of insulin resistance by macrophage-derived factors are conserved between insects and mammals. Chronic insulin resistance is at the base of many human metabolically conditioned diseases such as non-alcoholic steatohepatitis, atherosclerosis, diabetes, and cachexia. Therefore, revealing the original biological relevance of cytokine-induced insulin resistance may help to develop a suitable strategy for treating these frequent diseases.

Keywords: Drosophila; aerobic glycolysis; cachexia; cytokines; immuno-metabolism; insulin resistance; macrophages.

FIGURE 1

Schematic representation of the “selfish immune system theory.” Infection-activated macrophages adopt Hif1α-induced aerobic glycolysis and subsequently release signaling factors to ensure sufficient amount of nutrients to supplement the immune function. Hif1α, hypoxia-inducible factor 1 α.

FIGURE 2

Representative confocal and electron microscopy images of Drosophila macropahges. (A) Adult Drosophila bearing a genetic construct that enables visualization of macrophages (in green HmlGal4 > UAS2xeGFP) and tissue expressing lactate dehydrogenase (LDH-mCherry). (B) Confocal image depicting growth of streptococcus in dissected Drosophila abdomen (green—S. pneumoniae, red pericardial cells, cyan—DAPI). (C) Confocal image depicting phagocytic events by injection of Drosophila adult with pHrodo^TM Red S. aureus Bioparticles^TM Conjugate. Macrophages are visualized by endogenously expressed GFP (Crq > GFP) (green—macrophages, red—phagolysosomes). (D) Confocal image depicting endocytosis of low-density lipoproteins by injection of adult fly with pHrodo^TM Red-LDL. Macrophages are visualized by endogenously expressed GFP (Crq > GFP) (green—macrophages, red—LDL-containing late endosomes). (E) ImpL2-expressing macrophages interacting with fluorescently labeled S. pneumoniae (green—S. pneumoniae, red—ImpL2 Gal4 > UAS mCherry, white—phalloidin). (F) Pseudo-colored scanning electron micrograph of a macrophage interacting with S. pneumoniae (green—macrophage, purple—S. pneumoniae). (G) Transmission electron micrograph of S. pneumoniae bacteria (white arrows) in a macrophage. Crq, croquemort; ImpL2, imaginal morphogenesis protein late 2; LDL, low-density lipoproteins; S.p., Streptococcus pneumoniae.

FIGURE 3

Schematic representation of the proposed hypothetical model. In infection-activated macrophages, HIF1α stabilization leads to adoption of aerobic glycolysis, which is a highly energy demanding metabolic program. Aerobic glycolysis is interconnected with the production of selfish immune factors. These molecules affect remotely the metabolism of the main storage organs via induction of insulin resistance, leading to FOXO nuclear translocation and induction of mobilization of sources. This results in elevated titer of circulating carbohydrates and lipids, which are thus utilized by bactericidal macrophages to supplement their increased energy demands. Such inter-organ communication is essential for resistance to infection by extracellular pathogen, but may be maladaptive upon its chronic activation or in case of infection by intracellular bacteria. Hif1α, hypoxia-inducible factor 1 α; FOXO, forkhead box O; Upd3, unpaired 3; ImpL2, Imaginal morphogenesis protein late 2; IGFBP7, insulin-growth factor binding protein 7; IL-6, interleukin 6; eAdo, extracellular adenosine; SIFs, selfish immune factors.