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Macrophage-derived insulin/IGF antagonist ImpL2 regulates systemic metabolism for mounting an effective acute immune response in Drosophila

Krejčová Gabriela, Bajgar Adam, Nedbalová Pavla, Kovářová Julie, Kamps-Hughes Nick, Zemanová Helena, Strych Lukáš, Doležal Tomáš

Preprint posted on September 25, 2020 https://www.biorxiv.org/content/10.1101/2020.09.24.311670v1

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.

HmlGFP, LDH-mCHerry fly demonstrating that activated macrophages employ aerobic glycolysis. Image kindly provided by the authors.

 

Key findings

  1.     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.

  1.     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

 

  1. 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?
  2. What impact do you think this metabolic adaption may have on hemocyte subtypes?
  3. 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

  1. O’Neill LAJ, Pearce EJ. Immunometabolism governs dendritic cell and macrophage function. J Exp Med. 2016 Jan 11;213(1):15–23.
  2. O’Neill LAJ, Kishton RJ, Rathmell J. A guide to immunometabolism for immunologists. Nat Rev Immunol. 2016;16(9):553–65.
  3. 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.
  4. Evans IR, Wood W. Drosophila embryonic hemocytes. Curr Biol CB. 2011 Mar 8;21(5):R173-174.
  5. 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.
  6. 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.

Tags: drosophila, hemocytes, immunity, insulin, macrophages, metabolism

Posted on: 18th November 2020 , updated on: 19th November 2020

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Author's response

Gabriela and Adam (on behalf of the collective of authors) shared

  1. 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?

Unfortunately, we have not investigated the changes in mitochondrial metabolism yet. We have just touched this topic in our previous publication where some selected TCA cycle enzymes were not transcriptionally changed in hemocytes upon acute phase of infection. However, this information is very sparse and does not provide much evidence about the TCA cycle. Indeed, exploring the mitochondrial metabolism in activated Drosophila macrophages would be of a great interest.

  1. What impact do you think this metabolic adaption may have on hemocyte subtypes?

Frankly, we do not know much about hemocyte subtypes in adult flies. It may be expected that there is certain functional variability in adult fly macropahges. For instance, it is clear from our data that not all macropahges react to infection by upregulation of ImpL2. From our previous publication we may say that not all macropahges perform phagocytosis and not all macrophages display increased consumption of glucose upon infection. The detail analysis of macropahges location show their close interaction with various tissues and organs. One may thus anticipate functional variability between these subpopulations. We expect that single cell transcriptomic will be employed in the research of this problematics soon.

 

  1. 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?

Overexpression of ImpL2 seems to be beneficial during acute infection, however, it is detrimental upon infection caused by intracellular pathogen, which progresses into chronic inflammation. We think that chronic inflammation is inevitably connected with wasting. We imagine unflagging mobilization of stores from fat body upon prolonged production of ImpL2, which subsequently causes wasting of nutrients. Nonetheless, whether the flies died because of wasting, deposition of excessive lipids in vital organs, or due to an excessive number of Listeria remains to be answered.

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