Metabolic strategy of macrophages under homeostasis or immune stress in Drosophila

Abstract

Macrophages are well known for their phagocytic functions in innate immunity across species. In mammals, they rapidly consume a large amount of energy by shifting their metabolism from mitochondrial oxidative phosphorylation toward aerobic glycolysis, to perform the effective bactericidal function upon infection. Meanwhile, they strive for sufficient energy resources by restricting systemic metabolism. In contrast, under nutrient deprivation, the macrophage population is down-regulated to save energy for survival. Drosophila melanogaster possesses a highly conserved and comparatively simple innate immune system. Intriguingly, recent studies have shown that Drosophila plasmatocytes, the macrophage-like blood cells, adopt comparable metabolic remodeling and signaling pathways to achieve energy reassignment when challenged by pathogens, indicating the conservation of such metabolic strategies between insects and mammals. Here, focusing on Drosophila macrophages (plasmatocytes), we review recent advances regarding their comprehensive roles in local or systemic metabolism under homeostasis or stress, emphasizing macrophages as critical players in the crosstalk between the immune system and organic metabolism from a Drosophila perspective.

Keywords: Drosophila; Immune system; Macrophage; Metabolism; Plasmatocyte.

Fig. 1

Drosophila hematopoiesis. The anterior (A)-posterior (P) and dorsal (D)-ventral (V) axes indicate the orientation of embryo/larva/adult, except the pupa is orientated with anterior to the upside and posterior to the downside. PSC posterior signaling center

Fig. 2

Drosophila hemocytes and their functions. ECM extracellular matrix, AMP antimicrobial peptides

Fig. 3

Macrophages alter local and systemic metabolisms upon infection in Drosophila. Upon infection, HIF-1α stabilization in activated macrophages locally promotes the metabolic switch toward the aerobic glycolysis for rapid energy production to support the effective phagocytosis. Pyruvate, the key metabolite of glucose, is generally transported into mitochondria and is converted into acetyl-CoA by pyruvate dehydrogenase (PDH) for participating in the TCA cycle. In the acute phase of infection, the mitochondrial transport of pyruvate and the following ATP production by oxidative phosphorylation are repressed. Instead, cytosolic pyruvate is converted into lactate by lactate dehydrogenase (LDH) coupled with high-speed ATP production. At the same time, the activated macrophages restrict systemic metabolisms to grab more nutrients by secreting multiple effectors. The extracellular adenosine released by macrophages is recognized or taken up by other tissues, promoting glucose production from glycogen stores and glucose release into the hemolymph. This process is negatively controlled by adenosine deaminase-related growth factor A (ADGF-A), which is also produced by macrophages and catalyzes the degradation of adenosine. As another important effector secreted from macrophages, Upd3/IL-6 amplifies JAK/STAT signaling in other tissues reducing their insulin sensitivity and glycogen storage

Fig. 4

Macrophage-associated interplay between metabolism and the immune system in Drosophila. During homeostasis, macrophages are maintained in a basal number and at a basal metabolic level, playing essential roles to regulate lipid storage and organism growth through Pvf/Pvr signaling and JAK/STAT signaling. However, under stress conditions due to infection or nutrition deficiency, the immune system and other tissues compete for energy metabolism. Upon infection, the energy is reassigned to the immune system by inhibiting systemic metabolisms, which supports the rapid amplification of the macrophage population to defend against the pathogens. Likewise, when the nutrition is limited, the energy is reallocated toward the metabolic processes to ensure the survivability of the organism, and the number of macrophages is suppressed to save nutrients