2015; 2: 1–6

Review article Open Access

Dave Boucher, Kaiwen W. Chen, Kate Schroder* Burn the house, save the day: pyroptosis in pathogen restriction

Abstract: Many programmed cell pathways are an important innate immune mechanism for combating essential for organogenesis, development, immunity and intracellular pathogens [3]. The existence of this unusual the maintenance of homeostasis in multicellular organisms. modality was first implied in 1992, when the Pyroptosis, a highly proinflammatory form of cell death, is Sansonetti laboratory observed that murine a critical innate immune response to prevent intracellular infected with the Gram-negative bacterium, Shigella infection. Pyroptosis is induced upon the activation flexneri, undergo a form of cell death similar to of proinflammatory within macromolecular [4]. The Falkow laboratory made similar observations in signalling platforms called . This article cells infected with a closely related pathogen, reviews our understanding of pyroptosis induction, the Typhimurium, reporting the presence of DNA degradation, function of inflammatory caspases in pyroptosis execution, changes in nuclear morphology and vacuole formation and the importance of pyroptosis for pathogen clearance. It [5]. In addition to these apoptosis-like features, Cookson also highlights the situations in which extensive pyroptosis and co-workers reported that cell death by such infected may in fact be detrimental to the host, leading to immune cell cells also presented features similar to necrosis [6]. These depletion or storm. Current efforts to understand cells formed membrane pores of 1-2.5 nm and displayed the beneficial and pathological roles of pyroptosis bring the swelling and Ca2+ influx, leading to membrane rupture promise of new approaches to fight infectious diseases. and the extracellular release of cellular contents. This unusual form of pathogen-induced cell death, containing Keywords: pyroptosis, , inflammasomes, hallmarks of both apoptosis and necrosis [6], was found pathogen control, immune evasion to be dependent on the activity of a proinflammatory protease, caspase-1 [5]. The term ‘pyroptosis’ was coined by Cookson and Brennan in 2001 to distinguish this form DOI 10.1515/infl-2015-0001 of cell death from apoptosis and necrosis [7]. Received Ocotber 20, 2014; accepted December 4, 2014

1 Introduction 2 Pyroptosis initiation by canonical Caspase-1 inflammasomes Regulated cell death was first described in 1964 by Lockshin and William and is an essential process to Caspase-1 is a protease that drives potent inflammatory maintain homeostasis in living organisms [1]. Decades responses. Caspase-1 consists of a N-terminal CARD of subsequent research uncovered multiple specialised domain, followed by a bipartite catalytic domain, forms of cell death such as apoptosis, , NETosis composed of large and small subunits [8]. The protease and pyroptosis [2]. Pyroptosis has recently emerged as is synthesized within the cell as an inactive monomeric zymogen (pro-caspase-1) and is activated upon formation of the inflammasome, a large molecular signalling complex *Corresponding author: Kate Schroder: Institute for Molecular that assembles upon sensing of microbial or endogenous- Bioscience, The University of Queensland, St Lucia 4072, Australia. derived danger molecules [9-12]. So-called canonical Tel: +61 7 3346 2058, Fax: +61 7 3346 2101, E-mail: K.Schroder@ inflammasomes are composed of a sensor molecule and imb.uq.edu.au caspase-1, and often include the common adaptor protein, Dave Boucher, Kaiwen W. Chen: Institute for Molecular Bioscience, The University of Queensland, St Lucia 4072, Australia ASC. Sensing of endogenous or pathogen-derived danger molecules occurs through one or more nucleotide-binding domain and leucine-rich repeat containing receptor (NLR)

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(e.g. NLRP1, NLRP3, or a collaboration between NLRC4 and so indirectly through an unresolved mechanism involving NAIP) or HIN-200 (e.g. AIM2) receptor family members. NLRP3 and caspase-1 [19]. Recent studies suggest that Detection of such signals drives the oligomerisation of caspase-11 is activated through a surprising mechanism the sensor protein into a multimeric hub that enables involving direct interaction between the pro-caspase-11 downstream recruitment and clustering of ASC. ASC CARD domain and LPS, triggering caspase dimerisation acts as a signal adaptor that, upon binding to the sensor and activation, within the so-called ‘non-canonical protein, recruits pro-caspase-1 to the complex. Pro- inflammasome’ complex [20]. This finding for caspase- caspase-1 clustering within the inflammasome complex 11 is the first to suggest that inflammatory caspase may enables its activation through homodimerisation, an perform dual functions, encompassing both ligand sensor essential and probably sufficient step for the acquisition and effector activities, within an inflammasome complex. of enzymatic activity, which may be further influenced by Caspase-4 and -5 are the human orthologs of murine self-cleavage [8, 13, 14]. Self-processing occurs between caspase-11, and are currently not well characterised. the large and the small subunit of caspase-1, and appears These caspases also shared the LPS-binding properties to be mandatory for caspase-1-directed maturation of of caspase-11 [20], implying activation through a similar the inflammasome target , IL-1β and IL-18. This mechanism. The limited literature on these human cleavage event may be associated with stabilisation of caspases suggests their activation by intracellular the active site, as reported for initiator apoptotic caspases pathogens, and proposes functions in triggering IL-18 [15]. In contrast, self-processing between the large and the production and pyroptosis in infected epithelial cells small subunits appeared dispensable for the initiation [21]. Studies from a transgenic mouse expressing human of pyroptosis, as wild-type and uncleavable mutants of caspase-4 implicated this caspase, like murine caspase- caspase-1 were equally able to trigger pyroptosis in murine 11, as an important mediator of endotoxin sensitivity [22]. macrophages [14]. Pyroptosis execution does however The evolution of multiple inflammatory caspases capable absolutely require the catalytic activity of caspase-1 [5, 14]. of pyroptosis initiation highlights the importance of this Caspase-1 is also cleaved in the linker between the CARD process as an anti-microbial defence strategy. domain and the catalytic domain, but the outcome of this cleavage event remains unclear. While the molecular events directing pyroptosis execution downstream of 4 Pyroptosis as a pathogen caspase-1 activation are currently unknown, it is widely clearance mechanism believed that this process involves proteolytic activation of specific pyroptotic death effector molecules, akin to Several important human pathogens establish an the pathways controlling apoptosis. We recently reported intracellular niche within host cells, where they can that caspase-1 activation in neutrophils selectively triggers proliferate and protect themselves from soluble immune cytokine processing without concomitant cell death, mediators. Gram-negative Salmonella spp, which cause suggesting that individual cell types may suppress the typhoid fever and gastroenteritis, is one such example availability of pyroptotic death effectors as a means to of an intracellular bacterium. Several studies have modulate cell viability at a site of challenge [16]. demonstrated clear functions for inflammasomes in controlling the replication of Salmonella, through cytokine activation and induction of pyroptosis [16, 23, 24]. 3 Pyroptosis initiation by other Pyroptosis of infected cells is emerging as an important inflammatory caspases mechanism of microbial clearance [24], in addition to host defence mechanisms coordinated by inflammasome- Emerging studies now suggest that other inflammatory dependent IL-1β [16], and IL-18 [23, 25]. caspases are also recruited to, and activated by, pyroptosis releases Salmonella from its intracellular inflammasomes. The inflammatory caspase sub-family replicative niche, and increases its susceptibility to is comprised of caspases-1, -4, -5, and -12 in humans and neutrophil-mediated extracellular destruction (Figure 1). -1, -11, and -12 in mice. Caspase-11 has gained considerable This mechanism also appears effective in limiting the attention in recent years, as it is activated upon intracellular replication of other intracellular pathogens, including delivery of bacterial (LPS), and is Legionella and Burkholderia [24]. In addition to removing implicated into endotoxemia [17, 18]. Like caspase-1, active the bacterial replicative niche, pyroptosis also passively caspase-11 triggers pyroptosis. Surprisingly, caspase-11 releases multiple alarmins [26, 27] such as ATP, IL-33 [28] appears unable to directly cleave cytokines, and only does and HMGB1 [29] to alert and recruit immune cells to the site

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Macrophages Neutrophils

IL-1β Neutrophil recruitment and Salmonella activation alarmins

IL-1β IL-1β

pro-IL-1β pro-IL-1β

Pyroptosis No Inflammasome ? Inflammasome Pyroptosis Active Activates unknown Active Casp1 Casp1 pyroptotic effector

Antimicrobial mechanisms (e.g. reactive oxygen species, antimicrobial peptides, neutrophil extracellular traps)

Figure 1: Macrophage and neutrophils together coordinate pathogen control, via macrophage pyroptosis and continued neutrophil viabi- lity. In macrophages, pathogen recognition by a cytosolic inflammasome sensor triggers inflammasome assembly, caspase-1 activation, cytokine maturation and pyroptotic death. Pyroptosis is presumably executed via proteolytic activation of an unknown pyroptotic effector protein, and serves to release intracellular microbes such as Salmonella Typhimurium to the extracellular space. Caspase-1-dependent release of cytokines (e.g. IL-1β) and alarmins (e.g. IL-1α) triggers neutrophil recruitment to the site of infection, where they sense pathogens and trigger inflammasome assembly. Inflammasome activation in neutrophils triggers caspase-1-dependent IL-1β production in a positive amplification loop to ensure neutrophil influx and activation. The inability of neutrophils to undergo pyroptotic death, presumably due to pyroptotic effector unavailability, allows IL-1β secretion to be sustained, and enables neutrophils to execute their potent anti-microbial functions to clear the infection. of infection [30]. The oligomeric form of the adaptor protein antimicrobial mechanisms. It is therefore not surprising ASC can also act as an unusual alarmin released during that many pathogens have devised strategies to block pyroptosis that can propagate inflammasome signalling pyroptosis. Most of the reported subversion strategies in surrounding macrophages [31, 32]. Pyroptotic cells are target inflammasome function or caspase activity, and reported to undergo lysosomal exocytosis [33] to release so target both cytokine processing and pyroptotic death. lysosomal antimicrobial peptides [34] that facilitate the For example, intracellular Salmonella evades recognition clearance of pathogens by recruiting neutrophils. by the NAIP-NLRC4 inflammasome by repressing the The ability to undergo pyroptotic death is not unique expression of bacterial ligands detected by this pathway to immune cells. For example, pyroptosis of the gut (e.g. bacterial flagellin and the Salmonella pathogenicity promotes the extrusion of infected cells into island-1 type 3 secretion system) [24]. Yersinia species the gut lumen, preventing Salmonella, and probably other limit the enzymatic activity of caspase-1 by secreting a pathogens, from transversing the epithelial barrier to pseudosubstrate inhibitor, YopM, to prevent pyroptosis invade the host [21, 35]. and limit cytokine production [36]. Shigella actively prevents caspase-4-dependent cell death by secreting OspC3, a direct and specific inhibitor of caspase-4 [37]. 5 Pyroptosis inhibition or evasion These examples illustrate the diverse strategies bacteria by pathogens employ to bypass host defence mechanisms. Viruses have also evolved strategies to subvert pyroptosis and Constant host-pathogen interactions have provided cell death more generally [38]. These strategies include selection pressure for pathogens to evolve and subvert host the generation of decoy molecules to limit inflammasome

Brought to you by | University of Queensland - UQ Library Authenticated Download Date | 4/9/15 1:05 AM 4 D. Boucher et al. activation and the production of protease inhibitors to pyroptosis in different settings. Identification of specific prevent inflammatory caspase activity, and are discussed pyroptotic effector(s) will be instrumental for such further in greater detail elsewhere [39]. investigation, as current genetic approaches do not allow Immune cells can also die through other programmed the outcomes of pyroptosis to be evaluated in isolation cell death pathways such as apoptosis and necroptosis, from other inflammasome-dependent functions in murine which are often initiated in parallel to pyroptosis, possibly models of disease. as a means to thwart microbial subversion of pyroptotic pathways. One clear example of a cellular backup plan to control pathogen proliferation following inflammasome 7 Concluding remarks activation is the concurrent activation of caspase-8 While the current literature documents the tremendous alongside caspase-1 within the ASC speck, leading to the importance of pyroptosis in mediating control of intracellular execution of apoptosis if pyroptosis is blocked [40, 41]. pathogens, many questions remain unanswered. One such question is the precise function of pyroptosis when cell 6 The dark side of pyroptosis in death is initiated by a non-microbial (sterile) signal, such as extracellular ATP. In addition, the molecular events that pathogen clearance initiate and regulate pyroptosis upon caspase activation are unknown and remain an exciting field of investigation. While pyroptosis is an important innate immune Further research is required to establish the requirement for mechanism to clear intracellular pathogens, under individual candidate caspase-1 substrates in the execution of some situations, pyroptotic death can also facilitate pyroptosis, as such knowledge may allow the development pathogenicity and drive immune pathologies. An excellent of targeted therapies for pyroptosis-driven pathologies. The example is the case of human immunodeficiency virus future development of drugs that selectively target individual (HIV) infection. Depletion of CD4 T cells is a hallmark inflammatory caspases will also yield great insight into of HIV pathophysiology, and is the main driver of pyroptosis mechanisms and function, and have potential for acquired immunodeficiency syndrome (AIDS) [42]. Two the treatment of human diseases. This potential is illustrated recent studies unravelled mechanisms of CD4 T cell in the suggested usage of a caspase-1 inhibitor to limit CD4 T depletion during HIV infection [43, 44]. The authors cell depletion during HIV infection. However, many pitfalls demonstrated that abortive HIV infection in quiescent plague pyroptosis research. The absence of a genetic mouse CD4 T cells triggered caspase-1-mediated pyroptosis. In model that specifically blocks pyroptosis considerably limits this scenario, pyroptosis of quiescent CD4 T cells does our ability to delineate pyroptosis functions in vivo. Moreover, not necessarily deprive HIV of its replicative niche, as discrepancies between the immune systems of humans and this cell population is not permissive for viral replication. mice [49], for example the low evolutionary similarity within HIV instead replicates in activated CD4 T cells, which inflammatory caspases [12], limit our full understanding of represent only a minority of the CD4 T cell population, pyroptosis in human health and disease. This highlights and die by apoptosis. Pyroptosis in quiescent CD4 T the necessity for future research examining pyroptosis cells promoted chronic CD4 T cell depletion, driving the mechanisms and functions in a context clearly relevant for progression of AIDS [43-45]. Another example in which humans and the pathogens to which we are exposed. pyroptosis may be detrimental is that of NLRP1a-mediated pyroptosis in haematopoietic progenitor cells during Acknowledgments: We are very grateful to members haematopoietic stress induced by chemotherapy or bone of Schroder lab for their critical reviewing of this marrow infection [46]. Although seemingly intended as manuscript. Dave Boucher and Kaiwen Chen are a mechanism to prevent infection of daughter cells from supported by a Fonds de Recherche du Québec en Santé compromised haematopoietic progenitor cells, chronic Fellowship and a ANZ Trustee Medical Research Program pyroptosis resulted in cytopenia and immunosuppression Postgraduate Scholarship, respectively. KS is supported [46, 47]. Lastly, caspase-11-mediated pyroptosis may by the National Health and Medical Research Council of drive lethal endotoxemia by mediating the release Australia (APP1023297 and APP1064945), an Australian of intracellular inflammatory mediators [17, 18, 48]. Research Council Future Fellowship (FT130100361), and Collectively, such observations highlight the potential for the Queensland Smart Futures Fund. The authors declare pyroptosis to mediate pathology under certain conditions. no conflict of interests. Nonetheless, more research is required to assess the balance of beneficial versus detrimental effects of

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