Drosophila macrophages switch to aerobic glycolysis to mount effective antibacterial defense

Krejčová, Gabriela; Danielová, Adéla; Nedbalová, Pavla; Kazek, Michalina; Strych, Lukáš; Chawla, Geetanjali; Tennessen, Jason M.; Lieskovská, Jaroslava; Jindra, Marek; Doležal, Tomáš; Bajgar, Adam

doi:10.7554/elife.50414

Cited by 86 publications

(109 citation statements)

References 67 publications

(91 reference statements)

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“…Cells of the innate immune system also sense microbial load, integrate metabolic inputs, and alter nutrient allocation and organismal growth when performing pathogenic clearance functions (3,30,31). These functions are very similar to roles performed by the fat body, and we hypothesize immune cells as regulators of metabolism and organismal metabolic homeostasis not only in conditions of immune challenge but also in homeostasis or modulating nutrient environments.…”

Section: Introductionmentioning

confidence: 81%

Immune Control of Animal Growth in Homeostasis and Nutritional Stress in Drosophila

et al. 2020

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A large body of research implicates the brain and fat body (liver equivalent) as central players in coordinating growth and nutritional homeostasis in multicellular animals. In this regard, an underlying connection between immune cells and growth is also evident, although mechanistic understanding of this cross-talk is scarce. Here, we explore the importance of innate immune cells in animal growth during homeostasis and in conditions of nutrient stress. We report that Drosophila larvae lacking blood cells eclose as small adults and show signs of insulin insensitivity. Moreover, when exposed to dietary stress of a high-sucrose diet (HSD), these animals are further growth retarded than normally seen in regular animals raised on HSD. In contrast, larvae carrying increased number of activated macrophage-like plasmatocytes show no defects in adult growth when raised on HSD and grow to sizes almost comparable with that seen with regular diet. These observations imply a central role for immune cell activity in growth control. Mechanistically, our findings reveal a surprising influence of immune cells on balancing fat body inflammation and insulin signaling under conditions of homeostasis and nutrient overload as a means to coordinate systemic metabolism and adult growth. This work integrates both the cellular and humoral arm of the innate immune system in organismal growth homeostasis, the implications of which may be broadly conserved across mammalian systems as well.

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Section: Introductionmentioning

confidence: 81%

Immune Control of Animal Growth in Homeostasis and Nutritional Stress in Drosophila

et al. 2020

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“…Immune-activated states: PM5 from our scRNA-seq data is enriched in several metabolic genes including gapdh2 and lactate dehydrogenase/Ldh, strongly suggesting that PM5 is metabolically active. It is known that hemocytes can elevate their rates of aerobic glycolysis and increase the levels of Ldh to mount an effective immune response against pathogenic bacteria and wasp eggs (Bajgar et al, 2015;Krejčová et al, 2019). Additionally, genes of the glutathione S-transferase family of metabolic enzymes, which are known to catalyze the conjugation of reduced glutathione (GSH) to xenobiotics for their ultimate degradation, are enriched in this state (Fig.…”

Section: Towards a Fly Blood Cell Atlas -Defining Cell Types And Statesmentioning

confidence: 99%

A single-cell survey ofDrosophilablood

Tattikota

Liu

et al. 2019

Preprint

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SummaryDrosophila blood cells, called hemocytes, are classified into plasmatocytes, crystal cells, and lamellocytes based on the expression of a few marker genes and cell morphologies, which are inadequate to classify the complete hemocyte repertoire. Here, we used single-cell RNA sequencing (scRNA-seq) to map hemocytes across different inflammatory conditions in larvae. We resolved plasmatocytes into different states based on the expression of genes involved in cell cycle, antimicrobial response, and metabolism together with the identification of intermediate states. Further, we discovered rare subsets within crystal cells and lamellocytes that express fibroblast growth factor (FGF) ligand branchless and receptor breathless, respectively. We demonstrate that these FGF components are required for mediating effective immune responses against parasitoid wasp eggs, highlighting a novel role for FGF signaling in inter-hemocyte crosstalk. Our scRNA-seq analysis reveals the diversity of hemocytes and provides a rich resource of gene expression profiles for a systems-level understanding of their functions.HighlightsscRNA-seq of Drosophila blood recovers plasmatocytes, crystal cells, and lamellocytesscRNA-seq identifies different plasmatocyte states based on the expression of genes involved in cell cycle regulation, antimicrobial response, and metabolismPseudotemporal ordering of single cells identifies crystal cell and lamellocyte intermediate statesscRNA-seq uncovers a novel role for FGF signaling in inter-hemocyte crosstalk

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“…For example, mice injected with lipopolysaccharide (LPS) or infected with Escherichia coli exhibit trade-offs in core temperature and metabolism to drive disease tolerance (Ganeshan et al, 2019). At the level of individual immune cells, immune signaling shifts glucose metabolism from oxidative phosphorylation to aerobic glycolysis; this switch promotes immune effector functions (Chang et al, 2013;Gleeson et al, 2016;Krawczyk et al, 2010;Krejčová et al, 2019). Metabolic changes allow promote the secretory functions of immune cells.…”

Section: Introductionmentioning

confidence: 99%

Innate immune signaling inDrosophilashifts anabolic lipid metabolism from triglyceride storage to phospholipid synthesis in an ER stress-dependent manner

Martínez

Bland

2020

Preprint

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During infection, cellular resources are allocated toward synthesis and secretion of effector proteins that neutralize and kill invading pathogens. In Drosophila, antimicrobial peptides (AMPs) are produced in the fat body, an organ that also serves as a major nutrient storage depot.Here we asked how the innate immune response activated by fat body Toll signaling alters lipid metabolism as a model for understanding how the cellular and energetic demands of the immune response are met. We find that genetic activation of fat body Toll signaling leads to a tissueautonomous reduction in triglyceride storage that is paralleled by decreased transcript levels of Lipin and midway, enzymes that carry out the final steps of triglyceride synthesis. In contrast, Kennedy pathway enzymes that synthesize phospholipids and their products, phosphatidylcholine and phosphatidylethanolamine, are induced in fat bodies with active Toll signaling. Induction of these enzymes depends on the unfolded protein response mediator Xbp1, and examination of endoplasmic reticulum (ER) morphology by transmission electron microscopy revealed significantly expanded ER in fat body cells with active Toll signaling.Together these results indicate that Toll signaling induces a metabolic switch from triglyceride storage to phospholipid synthesis and ER expansion; this occurs in response to AMP production and may sustain AMP synthesis and secretion during infection. Better understanding of how this anabolic switch in lipid metabolism is induced, as well as the long-term consequences of reduced triglyceride storage at the expense of phospholipid synthesis, should yield insight into metabolic diseases that stem from chronic inflammation.

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Drosophila macrophages switch to aerobic glycolysis to mount effective antibacterial defense

Cited by 86 publications

References 67 publications

Immune Control of Animal Growth in Homeostasis and Nutritional Stress in Drosophila

Immune Control of Animal Growth in Homeostasis and Nutritional Stress in Drosophila

A single-cell survey ofDrosophilablood

Innate immune signaling inDrosophilashifts anabolic lipid metabolism from triglyceride storage to phospholipid synthesis in an ER stress-dependent manner

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