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Pyroptosis Versus Necroptosis: Similarities, Differences, and Crosstalk

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Pyroptosis Versus Necroptosis: Similarities, Differences, and Crosstalk Cell Death & Differentiation (2019) 26:99–114 https://doi.org/10.1038/s41418-018-0212-6 REVIEW ARTICLE Pyroptosis versus necroptosis: similarities, differences, and crosstalk 1,2 1,2 Daniel Frank ● James E. Vince Received: 9 June 2018 / Revised: 17 August 2018 / Accepted: 20 September 2018 / Published online: 19 October 2018 © ADMC Associazione Differenziamento e Morte Cellulare 2018 Pyroptosis and necroptosis represent two pathways of genetically encoded necrotic cell death. Although these cell death programmes can protect the host against microbial pathogens, their dysregulation has been implicated in a variety of autoimmune and auto-inflammatory conditions. The disease-promoting potential of necroptosis and pyroptosis is likely a consequence of their ability to induce a lytic cell death. This cell suicide mechanism, distinct from apoptosis, allows the release of immunogenic cellular content, including damage-associated molecular patterns (DAMPs), and inflammatory cytokines such as interleukin-1β (IL-1β), to trigger inflammation. In this Review, we discuss recent discoveries that have advanced our understanding on the primary functions of pyroptosis and necroptosis, including evidence for the specific cytokines and DAMPs responsible for driving inflammation. We compare the similar and unique aspects of pyroptotic- and necroptotic-induced membrane damage, and explore how these may functionally impact distinct intracellular organelles and signalling pathways. We also examine studies highlighting the crosstalk that can occur between necroptosis and pyroptosis 1234567890();,: 1234567890();,: signalling, and evidence supporting the physiological significance of this convergence. Ultimately, a better understanding of the similarities, unique aspects and crosstalk of pyroptosis and necroptosis will inform as to how these cell death pathways might be manipulated for therapeutic benefit. Facts Open Questions ● Pyroptosis and necroptosis are lytic, inflammatory types ● Are there DAMPs that are released that are unique to of programmed cell death that require the membrane pyroptosis and necroptosis? damaging GSDMD and MLKL proteins, respectively. ● What are the key necroptotic and pyroptotic DAMPs ● Pyroptosis and necroptosis protect against infections and that contribute to inflammatory responses? can be triggered by pathogen and host molecules. ● Does MLKL-induced NLRP3 inflammasome activity ● A number of DAMPs are released by pyroptotic and contribute to necroptotic-induced inflammatory disease? necroptotic cell death, which have the capacity to trigger ● How critical are GSDMD membrane pores for IL-1β inflammatory responses. release and inflammatory responses in different diseases? ● GSDMD and MLKL signalling both cause potassium efflux to trigger the NLRP3 inflammasome, resulting in IL-1β-driven inflammation. Introduction The idea of cells equipped with an internal instruction manual to die was first proposed back in 1965 from the study of developing insect cells [1]. Since then, exten- Edited by F. Pentimalli sive research has been carried out and has shed light on the significance and the mechanism of programmed cell death. * James E. Vince It is now established that cells can commit suicide, [email protected] either during development, as a consequence of pathogen 1 The Walter and Eliza Hall Institute of Medical Research, 1G Royal invasion, or following cellular stress and metabolic dis- Parade, Melbourne, VIC 3052, Australia turbances. The three genetically defined cell death pathways 2 Department of Medical Biology, The University of Melbourne, that have been intensively investigated in recent years are Parkville, VIC 3050, Australia apoptosis, necroptosis, and pyroptosis. 100 D. Frank, J. E. Vince Fig. 1 Gasdermins form membrane pores to cause pyroptosis. A wide GSDMD-N pores promote the release of activated IL-1β and IL-18 array of extracellular stimuli can drive pyroptosis. In the canonical and, most likely, DAMPs that can be accommodated by the 10–20 nm model of pyroptosis, inflammasome sensor proteins, such as NLRP3, pore diameter. Additional DAMPs will be released following the recognize cellular stressors, including those from bacteria, viruses, collapse of the plasma membrane. Cytosolic LPS binds Caspase-4/5/ toxins, ATP, uric acid crystals, silica, and DAMPs. These stressors 11 to trigger their cleavage of GSDMD, but not IL-1β and IL-18. In activate NLRP3 indirectly through potassium efflux, which leads to addition, recent research has revealed how the apoptotic effector cas- NEK7 binding NLRP3 to trigger its oligomerization. pase, caspase-3, can cleave GSDME to also cause pyroptotic NLRP3 subsequently activates caspase-1 via the adaptor protein ASC. death. DAMPs damage-associated molecular patterns, LPS Caspase-1 processes and activates IL-1β and IL-18, and also cleaves lipopolysaccharide GSDMD to release the membrane pore-forming GSDMD-N domain. Apoptosis was the first programmed cell death An overview of pyroptosis described [2], and in most cases apoptotic effectors such as caspase-3 and -7 ensure that it remains immunologi- The act of pyroptosis was first described in 1992 [17], but cally silent [3–6]. In contrast, necroptosis and pyroptosis the term was coined in 2001 following the observation that are lytic cell death modalities that allow the release of bacteria-infected macrophages underwent a rapid lytic cell potential immunostimulatory molecules. Genetic evi- death dependent on caspase-1 activity [18]. Although tra- dence supports the idea that, when activated, these cell ditionally defined as caspase-1-mediated cell death, studies death pathways can induce potent inflammatory respon- have revealed other caspases, caspase-11 and its human sesinvivo,andtherebymaycontributetovarious orthologs caspase-4 and -5 [19, 20], and more recently the inflammatory disease pathologies [7–10]. However, it is apoptotic effector caspase, caspase-3 [21, 22], as being worth considering that the act of cell death, regardless of capable of triggering pyroptosis (Fig. 1). its mechanism, will invariably abrogate cell-intrinsic The execution of pyroptotic cell death via these caspases inflammatory cytokine production. This may reflect is a result of their ability to cleave and activate specific cell-type and stimulus-specific pyroptotic and necroptotic members of the pore-forming gasdermin gene family, which signalling scenarios and therefore, in some circum- incorporates six genes in humans and ten in mice. To date, stances, the bystander DAMPs released following pyr- caspase-1/4/5/11 have been reported to target gasdermin D optosis and necroptosis may be less inflammatory than if (GSDMD) [23, 24], while caspase-3 can process gasdermin the cell did not receive the cues for suicide [11–16]. In E (GSDME/DFNA5) [21, 22]. Gasdermin N- and C- this Review, we focus on the immunogenic nature of terminal linker domain cleavage releases an activated N- necroptosis and pyroptosis. We compare the similarities terminal region from an inhibitory C-terminal fragment. As and differences in how the necroptotic and pyroptotic such, expression of the gasdermin-N domain alone from effectors induce membrane damage, and the mounting GSDMA, GSDMA3, GSDMB, GSDMAC, GSDMD and evidence documenting how these modes of cell death GSDME can signal cell death [23, 25], although proteases allow the subsequent release of inflammatory cytokines that might target GSDMA to GSDMC, and the physiolo- and DAMPs. We also discuss emerging studies suggest- gical functions of these gasdermins, requires further study. ing that necroptotic crosstalk with the pyroptotic Nevertheless, a body of evidence supports the idea that machinery may significantly contribute to the necroptotic when released by proteolysis, the gasdermin-N domain inflammatory response. binds to acidic phospholipids, such as phsophoinositides Pyroptosis versus necroptosis: similarities, differences, and crosstalk 101 found on the inner leaflet of the mammalian plasma mem- brane, to form oligomeric death-inducing pores [25–28]. In vitro studies also suggest that gasdermins can target bac- terial membranes to cause lysis, although in vivo reports indicate that bacteria survive the act of pyroptosis and are cleared by neutrophils [31, 32]. Regardless, we can now define mammalian cell pyroptosis as being gasdermin- dependent. In the canonical model of caspase-1-mediated pyroptosis, recognition of inflammatory ligands leads to activation of intracellular multiprotein signalling complexes known as the inflammasomes (Fig. 1). Among the best studied inflammasome sensors are absent in melanoma 2 (AIM2), Pyrin, and the NOD-like receptor (NLR) family members, NLRP1, NLRP3, and NLRC4 [33]. The AIM2 inflamma- Fig. 2 Membrane-associated MLKL induces necroptosis. Necroptosis fi can be triggered by death receptors (e.g. TNFR1), the IFNR, and some, for example, binds speci cally to, and is activated by, TLR3/4, which promote the assembly of a RIPK1-RIPK3-MLKL cytosolic double-stranded DNA. On the other hand, the signalling complex. RIPK3-mediated phosphorylation of MLKL NLRP3 inflammasome responds to a diverse set of mole- results in MLKL translocation to the plasma membrane to induce cules, such as ATP, crystalline (e.g. cholesterol crystals) membrane damage. Damaged membrane shedding, and cell death, is limited by the ESCRT-III complex. Recent findings have documented and viral components which, with few exceptions, trigger additional necroptotic triggers, such as BH3-mimetic (ABT-737)- NLRP3 activity by causing potassium efflux and subsequent induced MOMP
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