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Pyroptosis in Pathogen Restriction 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 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. cell death modality was first implied in 1992, when the Pyroptosis, a highly proinflammatory form of cell death, is Sansonetti laboratory observed that murine macrophages 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 apoptosis of proinflammatory caspases within macromolecular [4]. The Falkow laboratory made similar observations in signalling platforms called inflammasomes. This article cells infected with a closely related pathogen, Salmonella 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 cytokine 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, caspase, 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, necroptosis, 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) © 2014 Dave Boucher et al. licensee De Gruyter Open. This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License. Brought to you by | University of Queensland - UQ Library Authenticated Download Date | 4/9/15 1:05 AM 2 D. Boucher et al. (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 cytokines, 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]. Macrophage 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 lipopolysaccharide (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 Brought to you by | University of Queensland - UQ Library Authenticated Download Date | 4/9/15 1:05 AM Pyroptosis in pathogen restriction 3 Macrophages
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