Burn the house, save the day: pyroptosis in pathogen ...

Inflammasome 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 death pathways are essential for organogenesis, development, immunity and the maintenance of homeostasis in multicellular organisms. Pyroptosis, a highly proinflammatory form of cell death, is a critical innate immune response to prevent intracellular infection. Pyroptosis is induced upon the activation of proinflammatory caspases within macromolecular signalling platforms called inflammasomes. This article reviews our understanding of pyroptosis induction, the function of inflammatory caspases in pyroptosis execution, and the importance of pyroptosis for pathogen clearance. It also highlights the situations in which extensive pyroptosis may in fact be detrimental to the host, leading to immune cell depletion or cytokine storm. Current efforts to understand the beneficial and pathological roles of pyroptosis bring the promise of new approaches to fight infectious diseases. Keywords: pyroptosis, caspase, pathogen control, immune evasion

inflammasomes,

DOI 10.1515/infl-2015-0001 Received Ocotber 20, 2014; accepted December 4, 2014

1 Introduction Regulated cell death was first described in 1964 by Lockshin and William and is an essential process to maintain homeostasis in living organisms [1]. Decades of subsequent research uncovered multiple specialised forms of cell death such as apoptosis, necroptosis, NETosis and pyroptosis [2]. Pyroptosis has recently emerged as

*Corresponding author: Kate Schroder: Institute for Molecular Bioscience, The University of Queensland, St Lucia 4072, Australia. Tel: +61 7 3346 2058, Fax: +61 7 3346 2101, E-mail: K.Schroder@ imb.uq.edu.au Dave Boucher, Kaiwen W. Chen: Institute for Molecular Bioscience, The University of Queensland, St Lucia 4072, Australia

an important innate immune mechanism for combating intracellular pathogens [3]. The existence of this unusual cell death modality was first implied in 1992, when the Sansonetti laboratory observed that murine macrophages infected with the Gram-negative bacterium, Shigella flexneri, undergo a form of cell death similar to apoptosis [4]. The Falkow laboratory made similar observations in cells infected with a closely related pathogen, Salmonella Typhimurium, reporting the presence of DNA degradation, changes in nuclear morphology and vacuole formation [5]. In addition to these apoptosis-like features, Cookson and co-workers reported that cell death by such infected cells also presented features similar to necrosis [6]. These cells formed membrane pores of 1-2.5 nm and displayed swelling and Ca2+ influx, leading to membrane rupture and the extracellular release of cellular contents. This unusual form of pathogen-induced cell death, containing hallmarks of both apoptosis and necrosis [6], was found 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 of cell death from apoptosis and necrosis [7].

2 Pyroptosis initiation by canonical Caspase-1 inflammasomes Caspase-1 is a protease that drives potent inflammatory responses. Caspase-1 consists of a N-terminal CARD domain, followed by a bipartite catalytic domain, composed of large and small subunits [8]. The protease 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 that assembles upon sensing of microbial or endogenousderived danger molecules [9-12]. So-called canonical inflammasomes are composed of a sensor molecule and caspase-1, and often include the common adaptor protein, 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 NAIP) or HIN-200 (e.g. AIM2) receptor family members. Detection of such signals drives the oligomerisation of the sensor protein into a multimeric hub that enables downstream recruitment and clustering of ASC. ASC acts as a signal adaptor that, upon binding to the sensor protein, recruits pro-caspase-1 to the complex. Procaspase-1 clustering within the inflammasome complex enables its activation through homodimerisation, an essential and probably sufficient step for the acquisition of enzymatic activity, which may be further influenced by self-cleavage [8, 13, 14]. Self-processing occurs between the large and the small subunit of caspase-1, and appears to be mandatory for caspase-1-directed maturation of the inflammasome target cytokines, IL-1β and IL-18. This cleavage event may be associated with stabilisation of the active site, as reported for initiator apoptotic caspases [15]. In contrast, self-processing between the large and the small subunits appeared dispensable for the initiation of pyroptosis, as wild-type and uncleavable mutants of caspase-1 were equally able to trigger pyroptosis in murine macrophages [14]. Pyroptosis execution does however absolutely require the catalytic activity of caspase-1 [5, 14]. Caspase-1 is also cleaved in the linker between the CARD domain and the catalytic domain, but the outcome of this cleavage event remains unclear. While the molecular events directing pyroptosis execution downstream of caspase-1 activation are currently unknown, it is widely believed that this process involves proteolytic activation of specific pyroptotic death effector molecules, akin to the pathways controlling apoptosis. We recently reported that caspase-1 activation in neutrophils selectively triggers cytokine processing without concomitant cell death, suggesting that individual cell types may suppress the availability of pyroptotic death effectors as a means to modulate cell viability at a site of challenge [16].

3 Pyroptosis initiation by other inflammatory caspases Emerging studies now suggest that other inflammatory caspases are also recruited to, and activated by, inflammasomes. The inflammatory caspase sub-family is comprised of caspases-1, -4, -5, and -12 in humans and -1, -11, and -12 in mice. Caspase-11 has gained considerable attention in recent years, as it is activated upon intracellular delivery of bacterial lipopolysaccharide (LPS), and is implicated into endotoxemia [17, 18]. Like caspase-1, active caspase-11 triggers pyroptosis. Surprisingly, caspase-11 appears unable to directly cleave cytokines, and only does

so indirectly through an unresolved mechanism involving NLRP3 and caspase-1 [19]. Recent studies suggest that caspase-11 is activated through a surprising mechanism involving direct interaction between the pro-caspase-11 CARD domain and LPS, triggering caspase dimerisation and activation, within the so-called ‘non-canonical inflammasome’ complex [20]. This finding for caspase11 is the first to suggest that inflammatory caspase may perform dual functions, encompassing both ligand sensor and effector activities, within an inflammasome complex. Caspase-4 and -5 are the human orthologs of murine caspase-11, and are currently not well characterised. These caspases also shared the LPS-binding properties of caspase-11 [20], implying activation through a similar mechanism. The limited literature on these human caspases suggests their activation by intracellular pathogens, and proposes functions in triggering IL-18 production and pyroptosis in infected epithelial cells [21]. Studies from a transgenic mouse expressing human caspase-4 implicated this caspase, like murine caspase11, as an important mediator of endotoxin sensitivity [22]. The evolution of multiple inflammatory caspases capable of pyroptosis initiation highlights the importance of this process as an anti-microbial defence strategy.

4 Pyroptosis as a pathogen clearance mechanism Several important human pathogens establish an intracellular niche within host cells, where they can proliferate and protect themselves from soluble immune mediators. Gram-negative Salmonella spp, which cause typhoid fever and gastroenteritis, is one such example of an intracellular bacterium. Several studies have demonstrated clear functions for inflammasomes in controlling the replication of Salmonella, through cytokine activation and induction of pyroptosis [16, 23, 24]. Pyroptosis of infected cells is emerging as an important mechanism of microbial clearance [24], in addition to host defence mechanisms coordinated by inflammasomedependent IL-1β [16], and IL-18 [23, 25]. Macrophage pyroptosis releases Salmonella from its intracellular replicative niche, and increases its susceptibility to neutrophil-mediated extracellular destruction (Figure 1). This mechanism also appears effective in limiting the replication of other intracellular pathogens, including Legionella and Burkholderia [24]. In addition to removing the bacterial replicative niche, pyroptosis also passively releases multiple alarmins [26, 27] such as ATP, IL-33 [28] and HMGB1 [29] to alert and recruit immune cells to the site


Pyroptosis in pathogen restriction

Macrophages

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Neutrophils

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Salmonella alarmins IL-1β

IL-1β

pro-IL-1β

pro-IL-1β

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Activates unknown pyroptotic effector

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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 viability. 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 ASC can also act as an unusual alarmin released during pyroptosis that can propagate inflammasome signalling in surrounding macrophages [31, 32]. Pyroptotic cells are reported to undergo lysosomal exocytosis [33] to release lysosomal antimicrobial peptides [34] that facilitate the clearance of pathogens by recruiting neutrophils. The ability to undergo pyroptotic death is not unique to immune cells. For example, pyroptosis of the gut epithelium promotes the extrusion of infected cells into the gut lumen, preventing Salmonella, and probably other pathogens, from transversing the epithelial barrier to invade the host [21, 35].

5 Pyroptosis inhibition or evasion by pathogens Constant host-pathogen interactions have provided selection pressure for pathogens to evolve and subvert host

antimicrobial mechanisms. It is therefore not surprising that many pathogens have devised strategies to block pyroptosis. Most of the reported subversion strategies target inflammasome function or caspase activity, and so target both cytokine processing and pyroptotic death. For example, intracellular Salmonella evades recognition by the NAIP-NLRC4 inflammasome by repressing the expression of bacterial ligands detected by this pathway (e.g. bacterial flagellin and the Salmonella pathogenicity island-1 type 3 secretion system) [24]. Yersinia species limit the enzymatic activity of caspase-1 by secreting a pseudosubstrate inhibitor, YopM, to prevent pyroptosis 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]. These examples illustrate the diverse strategies bacteria employ to bypass host defence mechanisms. Viruses have also evolved strategies to subvert pyroptosis and cell death more generally [38]. These strategies include the generation of decoy molecules to limit inflammasome


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activation and the production of protease inhibitors to prevent inflammatory caspase activity, and are discussed in greater detail elsewhere [39]. Immune cells can also die through other programmed cell death pathways such as apoptosis and necroptosis, which are often initiated in parallel to pyroptosis, possibly as a means to thwart microbial subversion of pyroptotic pathways. One clear example of a cellular backup plan to control pathogen proliferation following inflammasome activation is the concurrent activation of caspase-8 alongside caspase-1 within the ASC speck, leading to the execution of apoptosis if pyroptosis is blocked [40, 41].

6 The dark side of pyroptosis in pathogen clearance While pyroptosis is an important innate immune mechanism to clear intracellular pathogens, under some situations, pyroptotic death can also facilitate pathogenicity and drive immune pathologies. An excellent example is the case of human immunodeficiency virus (HIV) infection. Depletion of CD4 T cells is a hallmark of HIV pathophysiology, and is the main driver of acquired immunodeficiency syndrome (AIDS) [42]. Two recent studies unravelled mechanisms of CD4 T cell depletion during HIV infection [43, 44]. The authors demonstrated that abortive HIV infection in quiescent CD4 T cells triggered caspase-1-mediated pyroptosis. In this scenario, pyroptosis of quiescent CD4 T cells does not necessarily deprive HIV of its replicative niche, as this cell population is not permissive for viral replication. HIV instead replicates in activated CD4 T cells, which represent only a minority of the CD4 T cell population, and die by apoptosis. Pyroptosis in quiescent CD4 T cells promoted chronic CD4 T cell depletion, driving the progression of AIDS [43-45]. Another example in which pyroptosis may be detrimental is that of NLRP1a-mediated pyroptosis in haematopoietic progenitor cells during haematopoietic stress induced by chemotherapy or bone marrow infection [46]. Although seemingly intended as a mechanism to prevent infection of daughter cells from compromised haematopoietic progenitor cells, chronic pyroptosis resulted in cytopenia and immunosuppression [46, 47]. Lastly, caspase-11-mediated pyroptosis may drive lethal endotoxemia by mediating the release of intracellular inflammatory mediators [17, 18, 48]. Collectively, such observations highlight the potential for pyroptosis to mediate pathology under certain conditions. Nonetheless, more research is required to assess the balance of beneficial versus detrimental effects of

pyroptosis in different settings. Identification of specific pyroptotic effector(s) will be instrumental for such further investigation, as current genetic approaches do not allow the outcomes of pyroptosis to be evaluated in isolation from other inflammasome-dependent functions in murine models of disease.

7 Concluding remarks While the current literature documents the tremendous importance of pyroptosis in mediating control of intracellular pathogens, many questions remain unanswered. One such question is the precise function of pyroptosis when cell death is initiated by a non-microbial (sterile) signal, such as extracellular ATP. In addition, the molecular events that initiate and regulate pyroptosis upon caspase activation are unknown and remain an exciting field of investigation. Further research is required to establish the requirement for individual candidate caspase-1 substrates in the execution of pyroptosis, as such knowledge may allow the development of targeted therapies for pyroptosis-driven pathologies. The future development of drugs that selectively target individual inflammatory caspases will also yield great insight into pyroptosis mechanisms and function, and have potential for the treatment of human diseases. This potential is illustrated in the suggested usage of a caspase-1 inhibitor to limit CD4 T cell depletion during HIV infection. However, many pitfalls plague pyroptosis research. The absence of a genetic mouse model that specifically blocks pyroptosis considerably limits our ability to delineate pyroptosis functions in vivo. Moreover, discrepancies between the immune systems of humans and mice [49], for example the low evolutionary similarity within inflammatory caspases [12], limit our full understanding of pyroptosis in human health and disease. This highlights the necessity for future research examining pyroptosis mechanisms and functions in a context clearly relevant for humans and the pathogens to which we are exposed. Acknowledgments: We are very grateful to members of Schroder lab for their critical reviewing of this manuscript. Dave Boucher and Kaiwen Chen are supported by a Fonds de Recherche du Québec en Santé Fellowship and a ANZ Trustee Medical Research Program Postgraduate Scholarship, respectively. KS is supported by the National Health and Medical Research Council of Australia (APP1023297 and APP1064945), an Australian Research Council Future Fellowship (FT130100361), and the Queensland Smart Futures Fund. The authors declare no conflict of interests.


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