Macrophage-derived insulin/IGF antagonist ImpL2 regulates systemic metabolism for mounting an effective acute immune response in Drosophila
Posted on: 18 November 2020 , updated on: 19 November 2020
Preprint posted on 25 September 2020
Hungry macrophages: Drosophila macrophages regulate systemic metabolism to provide fuel for immune responses
Selected by Jonny Coates
Categories: cell biology, immunology
Metabolism is intrinsically linked with the immune system (1,2). In recent years, it has been revealed that activated immune cells (primarily pro-inflammatory, M1-macrophages) alter their energy usage towards a pro-glycolytic (aerobic) metabolism. This gives the immune cells extra energy which is required for them to perform phagocytic functions, increase creation and release of cytokines and perform other key functions. Perhaps the best characterised metabolic adaptions are those in macrophages where there is an increase in enzymes involved in glycolysis and a number of “breaks” in the TCA cycle (3).
The alterations in metabolism are responsible for driving wider, transcriptional changes in the immune cells. For example, alterations in metabolism can result in cells becoming hypoxic (due to the increased use of oxygen and the limited oxygen concentration within the tissues where these cells are acting) which induces HIF-1α transcriptional programming.
Drosophila melanogaster (fruit fly) has been used as a model organism for over 100 years. Drosophila possess immune cells (hemocytes) that are functionally equivalent to macrophages (4,5). In a previous paper, the authors demonstrated that hemocytes are similarly capable of dramatic shifts in metabolism. However, this is still an emerging field in Drosophila research.
Key findings
- ImpL2 is increased in response to infection and is essential for survival
Following S. pneumoniae infection, the numbers of hemocytes producing ImpL2 in the adult were increased. In addition, the authors found that transcript levels of the insulin/IGF antagonist ImpL2 were increased following infection with S. pneumoniae. Intriguingly, ImpL2 expression was dependent on HIF-1α signalling (similarly, there is evidence that HIF-1α regulates metabolism in vertebrate macrophages, though ImpL2 has not yet been implicated). Further still, in flies lacking ImpL2 survival was reduced when they were challenged with S. pneumoniae infection.
- ImpL2 alters adipose tissue metabolism, providing fuel for hemocyte functions
ImpL2 was found to increase the levels of circulating carbohydrates and cholesterols by acting upon the fat body (an organ akin to the vertebrate liver). Following infection, genes involved in mobilization of lipids from adipose tissue are elevated, a transcriptional programme that appears to be mediated by FOXO.
Importance of this work / how it moves the field forward
This work follows from another excellent preprint (now published) by the same group (6) in which they demonstrated that Drosophila macrophages switch to glycolytic metabolism in response to infection. I chose this preprint as my PhD work was based around Drosophila macrophage heterogeneity (5) where I also developed interests in metabolism within the immune system. Metabolism is such a key process in polarising macrophages that these studies are significant advances and reveal just how fundamental these processes are throughout evolution.
Open questions
- Vertebrate macrophages (M1/pro-inflammatory phenotypes) are known to experience “breaks” in the TCA cycle (for example increased levels of succinate or itaconate). Is this something you have observed in hemocytes / have you explored the TCA cycle in hemocytes?
- What impact do you think this metabolic adaption may have on hemocyte subtypes?
- You show that overexpression of ImpL2 is detrimental to the host. Did you investigate if this led to wasting in the adults or was this due to a prolonged chronic inflammation?
References
- O’Neill LAJ, Pearce EJ. Immunometabolism governs dendritic cell and macrophage function. J Exp Med. 2016 Jan 11;213(1):15–23.
- O’Neill LAJ, Kishton RJ, Rathmell J. A guide to immunometabolism for immunologists. Nat Rev Immunol. 2016;16(9):553–65.
- Mills EL, Kelly B, Logan A, Costa ASH, Varma M, Bryant CE, et al. Succinate Dehydrogenase Supports Metabolic Repurposing of Mitochondria to Drive Inflammatory Macrophages. Cell. 2016 Oct 6;167(2):457-470.e13.
- Evans IR, Wood W. Drosophila embryonic hemocytes. Curr Biol CB. 2011 Mar 8;21(5):R173-174.
- Coates JA, Brittle A, Armitage EL, Zeidler MP, Evans IR. Identification of functionally-distinct macrophage subpopulations regulated by efferocytosis in Drosophila. bioRxiv. 2020 Apr 18;2020.04.17.047472.
- Krejčová G, Danielová A, Nedbalová P, Kazek M, Strych L, Chawla G, et al. Drosophila macrophages switch to aerobic glycolysis to mount effective antibacterial defense. Banerjee U, Banerjee U, Theopold U, editors. eLife. 2019 Oct 14;8:e50414.
doi: https://doi.org/10.1242/prelights.25744
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