All animals must be able to detect and repair injuries quickly. To do this, the body triggers a process called inflammation at the site of injury to remove dead and damaged cells, keep the area free from infection and trigger repair. However, if an area becomes excessively inflamed, or remains inflamed for a long period of time, it can contribute to diseases like cancer and Alzheimer’s disease.

Inflammation starts when the body detects molecules that are released when cells die or are damaged to the extent that they become leaky. Actin, which is a protein that usually provides structural support to the cell, is one molecule that is sensed by the immune system in mammals when released from dying cells. However, it is not clear whether released actin can also trigger reactions in simpler animals like fruit flies.

To address this question, Srinivasan, Gordon et al. injected fruit flies with actin. These animals developed a widespread reaction reminiscent of inflammation seen in mammals. Further experiments showed that actin switches on a signalling pathway called JAK/STAT, which is known to become active when flies experience other types of stress. The JAK/STAT proteins activate a signalling pathway that leads to changes in gene activity. Srinivasan, Gordon et al. also showed that part of a cascade of signals triggered by released actin in mammals is shared in fruit flies.

These findings suggest that this important response to actin evolved a long time ago. A future challenge is to find out how the body detects and mops up released actin, which may help us to understand how actin can contribute to various inflammatory diseases.

Trauma, burns, ischemia, strenuous exercise, all induce a sterile inflammatory response. It is likely that this response evolved to clear cell debris, promote tissue repair and maintain tissue sterility (Zelenay and Reis e Sousa, 2013; Eming et al., 2014) but, if uncontrolled, it can lead to (aseptic) shock and, in some cases, death (Rock et al., 2010). The prevailing notion is that sterile inflammation is initiated by pro-inflammatory signals that are released by damaged cells. These include intracellular components that are exposed when cells lose their membrane integrity, such as ATP, uric acid, RNA and DNA, collectively known as damage-associated molecular patterns (DAMPs) (Rock et al., 2010; Zelenay and Reis e Sousa, 2013). The universe of DAMPs and their receptors, as well as the mechanisms regulating DAMP responses, remains underexplored. This is partly because early research in this area was tainted by issues of microbial contamination (Beg, 2002) and because immunologists have often focussed on sterile inflammation from the narrow perspective of adaptive immunity (Matzinger, 1994; Land et al., 1994). However, it is probable that responses to DAMPs, like responses to microbes, pre-date the vertebrate evolution of T and B cells and have an early metazoan origin, much like the clearance of dead cells (Krysko et al., 2011; Hochreiter-Hufford and Ravichandran, 2013; Eming et al., 2014). Therefore, the study of invertebrate responses to DAMPs could offer a different perspective into the induction of sterile inflammation, akin to how research into insect immunity to infection led to the identification of Toll signalling and paved the way to the discovery of an analogous pathway in vertebrates (Lemaitre et al., 1996).

The immune system of Drosophila melanogaster has been widely studied in the context of infection. It consists of a cellular and a humoural arm, in addition to cell-intrinsic antiviral RNAi responses (Buchon et al., 2014; Lemaitre and Hoffmann, 2007). The cellular arm is made up of three macrophage-like types of cells, collectively termed haemocytes (Buchon et al., 2014; Lemaitre and Hoffmann, 2007). The humoural immune response relies on antimicrobial peptides (AMPs) that are synthesised in the fat body (the fly equivalent of the liver) and then secreted into the haemolymph to provide systemic protection from bacteria and fungi (Lemaitre and Hoffmann, 2007; Buchon et al., 2014). The production of AMPs is regulated by two different pathways. The Toll pathway is activated by peptidoglycan fragments of Gram-positive bacteria, fungal β-glucans, and pathogen-derived protease activity in the haemolymph (Buchon et al., 2014; Lemaitre and Hoffmann, 2007). The Imd pathway is activated by peptidoglycan fragments from Gram-negative bacteria (Buchon et al., 2014; Lemaitre and Hoffmann 2007). Activation of either pathway results in the translocation of distinct NF-κB family transcription factors into the nucleus and the subsequent synthesis of AMPs best suited to neutralise the type of microorganism detected (Lemaitre and Hoffmann, 2007; Buchon et al., 2014). A third pathway contributing to Drosophila humoural immunity involves Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signalling. In contrast to the Toll and Imd pathway, the JAK/STAT pathway has not yet been shown to be directly induced by sensors of invading microorganisms (Myllymäki and Rämet, 2014). However, it has been implicated in resistance to as well as tolerance to viral infections (Dostert et al., 2005; Lamiable et al., 2016). Notably, the JAK/STAT pathway is activated by different types of stresses (e.g. heat, mechanical pressure, oxidative stress or UV irradiation) (Lemaitre et al., 1996; Ekengren et al., 2001; Ekengren and Hultmark, 2001). All of these insults likely result in cell death suggesting the possibility that JAK/STAT pathway activation might be triggered by DAMPs rather than microbes.

The JAK/STAT pathway is elicited by cytokines of the Unpaired (Upd) family – Upd1 (Harrison et al., 1998), Upd2 (Gilbert et al., 2005; Hombría et al., 2005) and Upd3 (Agaisse et al., 2003; Wright et al., 2011) – all of which serve as ligands for the only JAK/STAT-coupled receptor in Drosophila, Domeless (dome) (Brown et al., 2001). The binding of Upds induces Domeless dimerization and activation of a single JAK (termed Hopscotch). Activated Hopscotch proteins phosphorylate one another allowing for recruitment of the single Drosophila STAT family transcription factor, STAT92E. The latter is then phosphorylated by Hopscotch, resulting in dimerisation and translocation into the nucleus. STAT92E dimers bind to the promoters of their target genes (Kiu and Nicholson, 2012; Bina et al., 2010; Müller et al., 2005) including, amongst others, ones encoding proteins involved in viral resistance (Lamiable et al., 2016; Dostert et al., 2005), as well as proteins of the Turandot family such as Turandot M (TotM). The exact function of Turandot family proteins is not known but they have been controversially argued to be linked to stress resistance (Ekengren and Hultmark, 2001; Ekengren et al., 2001; Mahapatra and Rand, 2012; Zhong et al., 2013). Besides a role in host defence, the JAK/STAT pathway has also been linked to energy metabolism (Rajan and Perrimon, 2012) and regenerative processes, for example in the gut (Jiang et al., 2009). The involvement of JAK/STAT signalling in regeneration is particularly interesting given the role of DAMPs in contributing to tissue repair (Vénéreau et al., 2015).

We have previously identified DNGR-1 (also known as CLEC9A) as a vertebrate-restricted innate immune receptor dedicated to DAMP recognition (Sancho et al., 2009). DNGR-1 is phosphorylated by Src family kinases and then signals via Syk although it does not induce inflammation. Rather, DNGR-1 is expressed by dendritic cells (DCs) and signals to favour cross-presentation of antigens from dead cells, contributing to CD8⁺ T cell responses to cytopathic infections and, possibly, tumours (Iborra et al., 2012; Zelenay et al., 2012; Sancho et al., 2009). We and others subsequently found that the DAMP recognised by DNGR-1 is F-actin, the polymer of G-actin that provides higher eukaryotic cells with structural integrity (Ahrens et al., 2012; Zhang et al., 2012). Actin is an ideal DAMP given that it is extremely conserved (90% identity between yeast and humans) and highly abundant and ubiquitous within all eukaryotic cells but absent from extracellular fluids. We therefore hypothesised that released actin constitutes an evolutionarily-conserved DAMP whose detection might involve a signalling pathway conserved from flies to mammals. This would be analogous to the conservation of the Toll signalling pathway (albeit not the upstream receptors) in the Drosophila and vertebrate response to fungi and bacteria. Here, we show systemic administration of actin to Drosophila selectively triggers a JAK/STAT response and that this requires the fly homologues of Src and Syk. Our data therefore reveal an evolutionarily-conserved tryosine kinase-based pathway for recognising damage through sensing of released or exposed actin.

Inflammation is a response to microbial invasion or tissue damage designed to eliminate the offending stimulus, clear debris and stimulate tissue repair. While we have learned much about the pathways that trigger inflammation in response to pathogen invasion (Medzhitov, 2010; Takeuchi and Akira, 2010), we still understand relatively little about induction of sterile inflammation following tissue injury (Rock et al., 2010). Importantly, dysregulated and/or chronic inflammation, often of sterile origin, is increasingly recognised as a contributing factor to a vast range of human diseases, from cancer to neurodegeneration (Okin and Medzhitov, 2012; Rock and Kono, 2008; Heneka et al., 2015; Zelenay and Reis e Sousa, 2013; Hanahan and Weinberg, 2011). Furthermore, because injury and infection often overlap, our understanding of immunity necessitates a consideration of the interplay between the processes that detect pathogen invasion and those that sense tissue damage. The study of invertebrate responses to DAMPs might therefore lead to a new understanding of sterile inflammation and the identification of conserved elicitors, detectors and signaling pathways that are utilised across evolution to detect loss of cell integrity.

We and others have previously reported that actin, one of the most abundant and conserved proteins in eukaryotic cells, acts as a DAMP in mouse and humans, binding to DNGR-1, a Src and Syk-coupled dead cell receptor expressed on DCs (Ahrens et al., 2012; Sancho et al., 2009; Zhang et al., 2012; Hanč et al., 2015). Here, we provide evidence that actin is also a DAMP in Drosophila melanogaster, triggering a response that, like in vertebrates, requires Syk and Src family kinases. We show that the presence of extracellular actin in the haemolymph of Drosophila elicits a reaction in the fat body via Shark and Src42A, whose activation depends on reactive oxygen species (ROS) generated by the NADPH oxidase Nox. Consistent with our data, ROS generation by NADPH oxidases is a highly conserved response to wounding (Nam et al., 2012; Takeishi et al., 2013) and has been shown to directly activate Lyn/Src42A in zebrafish and Drosophila through oxidation of a single redox-sensitive cysteine residue (Yoo et al., 2011; Niethammer et al., 2009; Evans et al., 2015; Razzell et al., 2013).

In contrast to DNGR-1 dependent recognition, the fly response to extracellular actin is elicited equally by G- and F-actin, does not require phagocytes but the fat body and its function is not to prime adaptive immunity, which is absent in invertebrates. Rather, it is coupled to production of Upd3 cytokine, which acts in an autocrine and paracrine manner to induce Domeless signalling via STAT and to cause the induction of STAT-responsive genes, the products of which are released into the haemolymph. This systemic inflammatory-like response involving cytokine amplification and the fat body is reminiscent of the acute phase response in mammals, which can be triggered by infection or trauma and leads to the production of cytokines such as IL-6 that act on the liver (mammalian equivalent of the fat body) to cause production of acute phase proteins (Medzhitov, 2010; Kopf et al., 1994). These are secreted into the plasma to regulate multiple processes such as host defence, coagulation, vascular permeability and metabolism (Medzhitov, 2010). Similarly, the Drosophila fat body response to actin results in secretion into the haemolymph of proteins that may regulate multiple aspects of fly physiology that coordinately impact resistance or tolerance to insult. However, it is important to note that while some components of the extracellular actin-sensing circuitry are conserved between flies and mammals (Shark, Src42A and ROS), others are not (DNGR1, cross-presentation, dendritic cells). These differences suggest that DAMPs can be more conserved than their receptors or the responses they evoke. This is akin to pathogen-associated molecular patterns (PAMPs) such as, for example, lipopolysaccharide (LPS), a hallmark of Gram-negative bacteria. The sensing of LPS is conserved in plants, protists and animals, but the relevant receptors and subsequent responses diverge depending on the host (Neyen et al., 2014). Similarly, peptidoglycans and β-glucans are used in both flies and mammals to signify bacterial or fungal presence, yet are detected by different receptors that, nevertheless, can couple to conserved signalling pathways.

The JAK/STAT pathway in Drosophila can be induced by mechanical pressure, heat shock, dehydration, cytopathic infection, septic wounds and other traumas (Ekengren et al., 2001; Agaisse et al., 2003; Pastor-Pareja et al., 2008; Dostert et al., 2005). How such seemingly disparate stimuli trigger a single pathway is puzzling. However, a common denominator in all these settings is cell death and it has been speculated that STAT activation might therefore occur in response to DAMP release (Shaukat et al., 2015; Buchon et al., 2014). Our data support that notion and suggest that actin is a potent DAMP for triggering the JAK/STAT pathway. Notably, pathogen infection in Anopheles gambiae and Drosophila melanogaster has been shown to lead to the release of actin into the haemolymph, where it can act as an antibacterial or antiparasitic agent (Vierstraete et al., 2004; Sandiford et al., 2015). Therefore, actin release may serve as a two-pronged defense mechanism, both directly as an antimicrobial and indirectly by activating a systemic JAK/STAT response.

The role of the systemic JAK/STAT response is unclear at present. Despite being commonly used as a marker of STAT activation, the function of Tot and Tep proteins in Drosophila is unknown. Nevertheless, genetic loss-of-function studies have implicated JAK/STAT signaling in resistance and/or tolerance to viral, bacterial and parasitoid infections (Yang et al., 2015; Agaisse et al., 2003; Agaisse and Perrimon, 2004; Brun et al., 2006; Dostert et al., 2005; Lamiable et al., 2016; Chakrabarti et al., 2016; Kemp et al., 2013; Merkling et al., 2015). Furthermore, the JAK/STAT pathway has a well-established role in maintenance of fly intestinal homeostasis, both at steady state and following infection or injury (Biteau et al., 2011; Kohlmaier et al., 2015; Jiang et al., 2009; Micchelli and Perrimon, 2006; Zhou et al., 2013; Osman et al., 2012; Jiang et al., 2011; Beebe et al., 2010; Lin et al., 2010; Zhai et al., 2015). Given these precedents, we attempted to investigate the role of the inducible actin-triggered JAK/STAT circuit by injecting actin into flies prior to challenge with viruses (Flock house virus, Drosophila C virus, Sindbis virus and Cricket paralysis virus) or bacteria (Erwinia carotovora, Escherichia coli, Micrococcus luteus and Listeria monocytogenes) but failed to find an effect on either resistance or tolerance to infection (data not shown). Similarly, in models of stress or injury (starvation, heat shock, irradiation, paraquat feeding and a recently-described model of concussion (Katzenberger et al., 2013, 2015)), we found no evidence of protection or susceptibility afforded by actin pre-injection (data not shown). Finally, we have also not found an effect of actin injection on fat body metabolism (data not shown). The failure to find a system in which prior upregulation of STAT target genes by exogenous actin leads to a difference in outcome is a current experimental limitation. However, it might reflect the fact that STAT activation is already induced to sufficient levels in those models in response to actin released from dying cells. Consistent with this notion, we observed that septic injury led to a rapid increase in actin levels within the haemolymph. In such a situation, additional induction of the STAT pathway by actin pre-injection may not confer additional protection or tolerance. Reinforcing this notion is a recent study showing that loss of basal Diedel levels leads to reduced tolerance to Sindbis virus, yet the upregulation of Diedel levels that takes place during infection is itself dispensable (Lamiable et al., 2016). Unfortunately, loss-of-function experiments to assess the effect of released actin on different challenges are not feasible because actin is essential for viability. Surrogate loss-of-function experiments, such as examining the role of Nox and Src42A or Shark in the fat body in the context of infection or injury, have not been reported and their interpretation is complicated by the pleiotropic effects of those proteins. Nevertheless, our finding that actin is released into the haemolymph upon septic injury and that this induces JAK/STAT activation dependent on fat body expression of Src42A and Nox may suggest that previous reports of septic injury-induced STAT activation can be partially ascribed to extracellular actin.

The identity of the putative receptor that recognises extracellular actin in Drosophila remains unknown. The requirement for Upd3 rules out the possibility that actin serves as a direct ligand for Domeless, a conclusion further supported by the fact that actin does not induce TotM upregulation in various Drosophila cell lines that respond to Upd cytokines in vitro (data not shown). Therefore, the simplest interpretation of our data is that Upd3 is synthesised by fat body cells that detect extracellular actin via a sensor(s) that couple(s) to a Nox-Src42A-Shark cascade (Figure 8—figure supplement 1). By analogy with other receptors that engage a Syk-dependent pathway, that sensor might be an ITAM- or hemITAM-bearing receptor or one that associates in trans with an ITAM-containing signalling chain (Brubaker et al., 2015; Robinson et al., 2009). Interestingly, in Drosophila responses to wounding and in the clearance of axonal debris and neuronal cell corpses, one such receptor is Draper, a member of the Nimrod family and orthologue of C. elegans Ced1. Draper contains an ITAM that is phosphorylated by Src42A (MacDonald et al., 2006; Ziegenfuss et al., 2008; Razzell et al., 2013; Evans et al., 2015). However, we have found Draper to be dispensable for TotM induction in response to actin injection. Similarly, we have not found a role for Nimrod C1, C4 and the scavenger receptor CD36 (data not shown). Whether these data indicate the activity of an unknown receptor, multiple redundant receptors or an indirect sensing mechanism, akin to the activation of the vertebrate NLRP3 receptor (Martinon et al., 2009), will need to be investigated.

In sum, our data suggest that extracellular actin released by dead cells induces a response in Drosophila that requires signalling in the fat body via the non-receptor tyrosine kinase, Shark, and the Src family kinase, Src42A. This pathway leads to production of Upd cytokines that act in an autocrine and paracrine manner to induce Domeless signalling via STAT and cause induction of STAT-responsive genes (Figure 8—figure supplement 1). Thus, the presence of actin in the extracellular space triggers a response previously associated with wounding and dead cell clearance, indicating that actin exposure acts as an ancient sign of tissue damage and that actin constitutes an evolutionarily-conserved DAMP. The notion that actin exposure can act as a universal sign of cell damage might apply more generally to other cytoskeletal proteins.

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Author details

1. Naren Srinivasan

   Immunobiology Laboratory, The Francis Crick Institute, London, United Kingdom

   Contribution

   NS, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Contributed equally with

   Oliver Gordon

   Competing interests

   The authors declare that no competing interests exist.

2. Oliver Gordon

   Immunobiology Laboratory, The Francis Crick Institute, London, United Kingdom

   Contribution

   OG, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Contributed equally with

   Naren Srinivasan

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0002-2567-2482

3. Susan Ahrens

   Immunobiology Laboratory, The Francis Crick Institute, London, United Kingdom

   Present address

   Voisin Consulting Life Sciences, Surrey, United Kingdom

   Contribution

   SA, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

4. Anna Franz

   Department of Biochemistry, Biomedical Sciences, University Walk, University of Bristol, Bristol, United Kingdom

   Contribution

   AF, Assistance with experiments, Acquisition of data

   Competing interests

   The authors declare that no competing interests exist.

5. Safia Deddouche

   Immunobiology Laboratory, The Francis Crick Institute, London, United Kingdom

   Present address

   Open Innovation Access Platform, Sanofi Strasbourg, Strasbourg, France

   Contribution

   SD, Assistance with experiments, Acquisition of data

   Competing interests

   The authors declare that no competing interests exist.

6. Probir Chakravarty

   Bioinformatics, The Francis Crick Institute, London, United Kingdom

   Contribution

   PC, Assistance with bioinformatics analysis

   Competing interests

   The authors declare that no competing interests exist.

7. David Phillips

   Genomics-Equipment Park, The Francis Crick Institute, London, United Kingdom

   Contribution

   DP, Assistance with experiments, Acquisition of data

   Competing interests

   The authors declare that no competing interests exist.

8. Ali A Yunus

   Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States

   Contribution

   AAY, Provided key reagents, Contributed unpublished essential data or reagents

   Competing interests

   The authors declare that no competing interests exist.

9. Michael K Rosen

   Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States

   Contribution

   MKR, Provided key reagents, Contributed unpublished essential data or reagents

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0002-0775-7917

10. Rita S Valente

    Instituto Gulbenkian de Ciência, Oeiras, Portugal

    Contribution

    RSV, Provided key reagents, Contributed unpublished essential data or reagents

    Competing interests

    The authors declare that no competing interests exist.

11. Luis Teixeira

    Instituto Gulbenkian de Ciência, Oeiras, Portugal

    Contribution

    LT, Provided key reagents, Contributed unpublished essential data or reagents

    Competing interests

    The authors declare that no competing interests exist.

    "This ORCID iD identifies the author of this article:" 0000-0001-8326-6645

12. Barry Thompson

    Epithelial Biology Laboratory, The Francis Crick Institute, London, United Kingdom

    Contribution

    BT, Conception and design, Analysis and interpretation of data

    Competing interests

    The authors declare that no competing interests exist.

    "This ORCID iD identifies the author of this article:" 0000-0002-0103-040X

13. Marc S Dionne

    Department of Life Sciences and MRC Centre for Molecular Bacteriology and Infection, South Kensington Campus, Imperial College London, London, United Kingdom

    Contribution

    MSD, Conception and design, Analysis and interpretation of data

    Competing interests

    The authors declare that no competing interests exist.

    "This ORCID iD identifies the author of this article:" 0000-0002-8283-1750

14. Will Wood

    Department of Cellular and Molecular Medicine, Biomedical Sciences, University of Bristol, Bristol, United Kingdom

    Competing interests

    The authors declare that no competing interests exist.

15. Caetano Reis e Sousa

    Immunobiology Laboratory, The Francis Crick Institute, London, United Kingdom

    Contribution

    CReS, Conception and design, Analysis and interpretation of data, Drafting or revising the article

    For correspondence

    caetano@crick.ac.uk

    Competing interests

    The authors declare that no competing interests exist.

    "This ORCID iD identifies the author of this article:" 0000-0001-7392-2119

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