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.

Prolonged Transcriptional Consequences in Survivors of Sepsis

“…Drosophila may ideal to study mechanism of action in sepsis but not for immediate clinical bedside testing. The Drosophila model provides striking similarity at the level of metabolomic response, monocyte polarization activation of several innate immunity pathways [ 21 , 23 , 28 , 30 , 31 , 38 , 39 , 44 , 45 ]. Activation of these mechanisms translates into abnormalities in the cardiovascular and neuronal system similar to those seen in septic shock of mammalian models [ 2 , 10 , 17 , 22 , 30 , 32 ].…”

“…Activation of these mechanisms translates into abnormalities in the cardiovascular and neuronal system similar to those seen in septic shock of mammalian models [ 2 , 10 , 17 , 22 , 30 , 32 ]. Drosophila models were instrumental in discovering several important immunological mechanisms and suggested future studies and treatments [ 1 , 2 , 17 , 22 , 25 , 28 , 31 , 37 , 40 , 44 ]. Most of the translation is indirect as the findings are fundamental and homologous in scientific and clinical nature [ 1 , 2 , 17 , 22 , 25 , 28 , 31 , 37 , 40 , 44 ].…”

“…Drosophila models were instrumental in discovering several important immunological mechanisms and suggested future studies and treatments [ 1 , 2 , 17 , 22 , 25 , 28 , 31 , 37 , 40 , 44 ]. Most of the translation is indirect as the findings are fundamental and homologous in scientific and clinical nature [ 1 , 2 , 17 , 22 , 25 , 28 , 31 , 37 , 40 , 44 ]. Finally, the introduction of bacteria may mimic bacteremia but not sepsis [ 2 , 7 , 22 , 27 ].…”

“…Several highly conservative pathways (p38, NFκB, Rel, ubiquitins) were of particular interest in Drosophila sepsis [ 21 , 29 , 30 ]. Monocytes, a critical component of sepsis response, showed typical sepsis polarization and cytokine activation in Drosophila [ 31 ]. In particular, the downstream activation of the interleukin-1 family closely resembles events seen in clinical settings [ 2 , 17 , 21 ].…”

Hematopoietic plasticity mapped in Drosophila and other insects

“…The geared-up metabolism in the lamellocytes may also be associated with a switch towards aerobic glycolysis in the lamellocytes, mediated by extracellular adenosine released from immune cells ( Bajgar et al, 2015 ), although that metabolic switch has been best studied in phagocytically activated plasmatocytes ( Bajgar and Dolezal, 2018 ; Krejčová et al, 2019 ; Bajgar et al, 2021 ). However, in agreement with a specific role of extracellular adenosine in lamellocyte hematopoiesis, the adenosine deaminase-related growth factor A ( Adgf-A ) and adenosine receptor ( AdoR ) transcripts are enriched in the lamellocytes ( Figure 1—source data 1 ).…”