Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Pyroptosis: host cell death and inflammation

Key Points

  • Life or death of individual cells determines health and disease in multi-celled organisms. Cell death is crucial for organogenesis in utero and successful control of host cell populations in healthy tissues, but can also play a part in disease that occurs in response to toxic insults or microbial infection.

  • The cysteine protease family called caspases is composed of both initiators and effectors, have crucial roles in cell death and drive mechanistically distinct modes of cellular demise. The physiological consequences of cell death are determined by the mechanisms employed, which range from relatively benign cellular destruction to alarm-ringing inflammatory recruitment of additional cells and biochemical processes.

  • Microorganism- and host-derived 'danger' signals stimulate formation of a multiprotein complex, termed the inflammasome, which leads to processing and activation of caspase 1. Active caspase 1 causes pyroptosis and is responsible for proteolytic maturation of the inflammatory cytokines interleukin-1β (IL-1β) and IL-18.

  • Pyroptosis is characterized by caspase 1-dependent formation of plasma-membrane pores, which leads to pathological ion fluxes that ultimately result in cellular lysis and release of inflammatory intracellular contents.

  • During microbial infection in vivo, caspase 1-dependent processes control pathogen replication, stimulate adaptive immune responses and enhance host survival; however, inappropriate activation of caspase 1 can lead to pathological inflammation.

  • Pathogens have a range of mechanisms for preventing the activation of caspase 1, highlighting its antimicrobial role during infection. Pathogens can directly inhibit caspase 1 activation, induce alternative forms of cell death or regulate production of caspase 1-activating ligands.

Abstract

Eukaryotic cells can initiate several distinct programmes of self-destruction, and the nature of the cell death process (non-inflammatory or proinflammatory) instructs responses of neighbouring cells, which in turn dictates important systemic physiological outcomes. Pyroptosis, or caspase 1-dependent cell death, is inherently inflammatory, is triggered by various pathological stimuli, such as stroke, heart attack or cancer, and is crucial for controlling microbial infections. Pathogens have evolved mechanisms to inhibit pyroptosis, enhancing their ability to persist and cause disease. Ultimately, there is a competition between host and pathogen to regulate pyroptosis, and the outcome dictates life or death of the host.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Pyroptosis, an inflammatory host response.
Figure 2: Sensing of host- and microorganism-derived 'danger' signals leads to two distinct outcomes: cellular activation and cell death.
Figure 3: Components of the inflammasome and visualizing the inflammasome complex.
Figure 4: Caspase 1 activation in health and disease: fighting infection versus pathological inflammation.
Figure 5: Susceptibility to pyroptosis is governed by pathogen and host modulation of caspase 1 activation.

References

  1. 1

    Samali, A., Zhivotovsky, B., Jones, D., Nagata, S. & Orrenius, S. Apoptosis: cell death defined by caspase activation. Cell Death Differ. 6, 495–496 (1999).

    CAS  PubMed  Google Scholar 

  2. 2

    Albert, M. L. Death-defying immunity: do apoptotic cells influence antigen processing and presentation? Nature Rev. Immunol. 4, 223–231 (2004).

    CAS  Google Scholar 

  3. 3

    Fink, S. L. & Cookson, B. T. Apoptosis, pyroptosis, and necrosis: mechanistic description of dead and dying eukaryotic cells. Infect. Immun. 73, 1907–1916 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    Frantz, S. et al. Targeted deletion of caspase-1 reduces early mortality and left ventricular dilatation following myocardial infarction. J. Mol. Cell. Cardiol. 35, 685–694 (2003).

    CAS  PubMed  Google Scholar 

  5. 5

    Fantuzzi, G. & Dinarello, C. A. Interleukin-18 and interleukin-1 beta: two cytokine substrates for ICE (caspase-1). J. Clin. Immunol. 19, 1–11 (1999).

    CAS  PubMed  Google Scholar 

  6. 6

    Brennan, M. A. & Cookson, B. T. Salmonella induces macrophage death by caspase-1-dependent necrosis. Mol. Microbiol. 38, 31–40 (2000).

    CAS  PubMed  Google Scholar 

  7. 7

    Fink, S. L. & Cookson, B. T. Caspase-1-dependent pore formation during pyroptosis leads to osmotic lysis of infected host macrophages. Cell. Microbiol. 8, 1812–1825 (2006). Mechanistic description of the features of pyroptosis, including the identification of caspase 1-dependent membrane pore formation, which leads to cell lysis.

    CAS  PubMed  Google Scholar 

  8. 8

    Hersh, D. et al. The Salmonella invasin SipB induces macrophage apoptosis by binding to caspase-1. Proc. Natl Acad. Sci. USA 96, 2396–2401 (1999).

    CAS  PubMed  Google Scholar 

  9. 9

    Chen, Y., Smith, M. R., Thirumalai, K. & Zychlinsky, A. A bacterial invasin induces macrophage apoptosis by binding directly to ICE. EMBO J. 15, 3853–3860 (1996). First description of caspase 1 activity that led to pathogen-induced cell death.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Hilbi, H. et al. Shigella-induced apoptosis is dependent on caspase-1 which binds to IpaB. J. Biol. Chem. 273, 32895–32900 (1998).

    CAS  PubMed  Google Scholar 

  11. 11

    Zhou, X. et al. Nitric oxide induces thymocyte apoptosis via a caspase-1-dependent mechanism. J. Immunol. 165, 1252–1258 (2000).

    CAS  PubMed  Google Scholar 

  12. 12

    Bergsbaken, T. & Cookson, B. T. Macrophage activation redirects Yersinia-infected host cell death from apoptosis to caspase-1-dependent pyroptosis. PLoS Pathog. 3, e161 (2007). This study demonstrated host redirection of cell death from apoptosis to pyroptosis in activated macrophages in response to Yersinia infection.

    PubMed  PubMed Central  Google Scholar 

  13. 13

    Cookson, B. T. & Brennan, M. A. Pro-inflammatory programmed cell death. Trends Microbiol. 9, 113–114 (2001).

    CAS  PubMed  Google Scholar 

  14. 14

    Li, P. et al. Mice deficient in IL-1β-converting enzyme are defective in production of mature IL-1β and resistant to endotoxic shock. Cell 80, 401–411 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Kuida, K. et al. Altered cytokine export and apoptosis in mice deficient in interleukin-1 beta converting enzyme. Science 267, 2000–2003 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Jesenberger, V., Procyk, K. J., Yuan, J., Reipert, S. & Baccarini, M. Salmonella-induced caspase-2 activation in macrophages: a novel mechanism in pathogen-mediated apoptosis. J. Exp. Med. 192, 1035–1046 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Kelk, P., Johansson, A., Claesson, R., Hanstrom, L. & Kalfas, S. Caspase 1 involvement in human monocyte lysis induced by Actinobacillus actinomycetemcomitans leukotoxin. Infect. Immun. 71, 4448–4455 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Sun, G. W., Lu, J., Pervaiz, S., Cao, W. P. & Gan, Y. H. Caspase-1 dependent macrophage death induced by Burkholderia pseudomallei. Cell. Microbiol. 7, 1447–1458 (2005).

    CAS  PubMed  Google Scholar 

  19. 19

    Cervantes, J., Nagata, T., Uchijima, M., Shibata, K. & Koide, Y. Intracytosolic Listeria monocytogenes induces cell death through caspase-1 activation in murine macrophages. Cell. Microbiol. 10, 41–52 (2008).

    CAS  PubMed  Google Scholar 

  20. 20

    Fink, S. L., Bergsbaken, T. & Cookson, B. T. Anthrax lethal toxin and Salmonella elicit the common cell death pathway of caspase-1-dependent pyroptosis via distinct mechanisms. Proc. Natl Acad. Sci. USA 105, 4312–4317 (2008). This study showed that distinct events which lead to caspase 1 activation, and ultimately cell death, occur through a common pathway of caspase 1-mediated pyroptosis.

    CAS  PubMed  Google Scholar 

  21. 21

    Thumbikat, P., Dileepan, T., Kannan, M. S. & Maheswaran, S. K. Mechanisms underlying Mannheimia haemolytica leukotoxin-induced oncosis and apoptosis of bovine alveolar macrophages. Microb. Pathog. 38, 161–172 (2005).

    CAS  PubMed  Google Scholar 

  22. 22

    Ren, T., Zamboni, D. S., Roy, C. R., Dietrich, W. F. & Vance, R. E. Flagellin-deficient Legionella mutants evade caspase-1- and Naip5-mediated macrophage immunity. PLoS Pathog. 2, e18 (2006).

    PubMed  PubMed Central  Google Scholar 

  23. 23

    Molofsky, A. B. et al. Cytosolic recognition of flagellin by mouse macrophages restricts Legionella pneumophila infection. J. Exp. Med. 203, 1093–1104 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Mariathasan, S., Weiss, D. S., Dixit, V. M. & Monack, D. M. Innate immunity against Francisella tularensis is dependent on the ASC/caspase-1 axis. J. Exp. Med. 202, 1043–1049 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    van der Velden, A. W., Velasquez, M. & Starnbach, M. N. Salmonella rapidly kill dendritic cells via a caspase-1-dependent mechanism. J. Immunol. 171, 6742–6749 (2003).

    CAS  PubMed  Google Scholar 

  26. 26

    Edgeworth, J. D., Spencer, J., Phalipon, A., Griffin, G. E. & Sansonetti, P. J. Cytotoxicity and interleukin-1β processing following Shigella flexneri infection of human monocyte-derived dendritic cells. Eur. J. Immunol. 32, 1464–1471 (2002).

    CAS  PubMed  Google Scholar 

  27. 27

    Monack, D. M., Raupach, B., Hromockyj, A. E. & Falkow, S. Salmonella typhimurium invasion induces apoptosis in infected macrophages. Proc. Natl Acad. Sci. USA 93, 9833–9838 (1996).

    CAS  PubMed  Google Scholar 

  28. 28

    Hilbi, H., Chen, Y., Thirumalai, K. & Zychlinsky, A. The interleukin 1β-converting enzyme, caspase 1, is activated during Shigella flexneri-induced apoptosis in human monocyte-derived macrophages. Infect. Immun. 65, 5165–5170 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Watson, P. R. et al. Salmonella enterica serovars Typhimurium and Dublin can lyse macrophages by a mechanism distinct from apoptosis. Infect. Immun. 68, 3744–3747 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Wickliffe, K. E., Leppla, S. H. & Moayeri, M. Killing of macrophages by anthrax lethal toxin: involvement of the N-end rule pathway. Cell. Microbiol. 10, 1352–1362 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Shao, W., Yeretssian, G., Doiron, K., Hussain, S. N. & Saleh, M. The caspase-1 digestome identifies the glycolysis pathway as a target during infection and septic shock. J. Biol. Chem. 282, 36321–36329 (2007).

    CAS  PubMed  Google Scholar 

  32. 32

    Matzinger, P. The danger model: a renewed sense of self. Science 296, 301–305 (2002).

    CAS  PubMed  Google Scholar 

  33. 33

    Kawai, T. & Akira, S. TLR signaling. Semin. Immunol. 19, 24–32 (2007).

    CAS  PubMed  Google Scholar 

  34. 34

    Kufer, T. A. & Sansonetti, P. J. Sensing of bacteria: NOD a lonely job. Curr. Opin. Microbiol. 10, 62–69 (2007).

    CAS  PubMed  Google Scholar 

  35. 35

    Martinon, F. & Tschopp, J. Inflammatory caspases and inflammasomes: master switches of inflammation. Cell Death Differ. 14, 10–22 (2007).

    CAS  PubMed  Google Scholar 

  36. 36

    Kahlenberg, J. M., Lundberg, K. C., Kertesy, S. B., Qu, Y. & Dubyak, G. R. Potentiation of caspase-1 activation by the P2X7 receptor is dependent on TLR signals and requires NF-κB-driven protein synthesis. J. Immunol. 175, 7611–7622 (2005).

    CAS  PubMed  Google Scholar 

  37. 37

    Le Feuvre, R. A., Brough, D., Iwakura, Y., Takeda, K. & Rothwell, N. J. Priming of macrophages with lipopolysaccharide potentiates P2X7-mediated cell death via a caspase-1-dependent mechanism, independently of cytokine production. J. Biol. Chem. 277, 3210–3218 (2002).

    CAS  PubMed  Google Scholar 

  38. 38

    Mariathasan, S. et al. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440, 228–232 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Gurcel, L., Abrami, L., Girardin, S., Tschopp, J. & van der Goot, F. G. Caspase-1 activation of lipid metabolic pathways in response to bacterial pore-forming toxins promotes cell survival. Cell 126, 1135–1145 (2006).

    CAS  PubMed  Google Scholar 

  40. 40

    Koo, I. C. et al. ESX-1-dependent cytolysis in lysosome secretion and inflammasome activation during mycobacterial infection. Cell. Microbiol. 10, 1866–1878 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Kanneganti, T. D. et al. Pannexin-1-mediated recognition of bacterial molecules activates the cryopyrin inflammasome independent of Toll-like receptor signaling. Immunity 26, 433–443 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Kanneganti, T. D. et al. Critical role for cryopyrin/Nalp3 in activation of caspase-1 in response to viral infection and double-stranded RNA. J. Biol. Chem. 281, 36560–36568 (2006).

    CAS  PubMed  Google Scholar 

  43. 43

    Martinon, F., Petrilli, V., Mayor, A., Tardivel, A. & Tschopp, J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440, 237–241 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Muruve, D. A. et al. The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response. Nature 452, 103–107 (2008).

    CAS  PubMed  Google Scholar 

  45. 45

    Kanneganti, T. D. et al. Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3. Nature 440, 233–236 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Dostert, C. et al. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science 320, 674–677 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Feldmeyer, L. et al. The inflammasome mediates UVB-induced activation and secretion of interleukin-1β by keratinocytes. Curr. Biol. 17, 1140–1145 (2007).

    CAS  PubMed  Google Scholar 

  48. 48

    Perregaux, D. et al. IL-1β maturation: evidence that mature cytokine formation can be induced specifically by nigericin. J. Immunol. 149, 1294–1303 (1992).

    CAS  PubMed  Google Scholar 

  49. 49

    Kahlenberg, J. M. & Dubyak, G. R. Mechanisms of caspase-1 activation by P2X7 receptor-mediated K+ release. Am. J. Physiol. Cell Physiol. 286, C1100–C1108 (2004).

    CAS  PubMed  Google Scholar 

  50. 50

    Franchi, L., Kanneganti, T. D., Dubyak, G. R. & Nunez, G. Differential requirement of P2X7 receptor and intracellular K+ for caspase-1 activation induced by intracellular and extracellular bacteria. J. Biol. Chem. 282, 18810–18818 (2007).

    CAS  PubMed  Google Scholar 

  51. 51

    Pelegrin, P. & Surprenant, A. Pannexin-1 couples to maitotoxin- and nigericin-induced interleukin-1β release through a dye uptake-independent pathway. J. Biol. Chem. 282, 2386–2394 (2007).

    CAS  PubMed  Google Scholar 

  52. 52

    Petrilli, V. et al. Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration. Cell Death Differ. 14, 1583–1589 (2007).

    CAS  PubMed  Google Scholar 

  53. 53

    Wickliffe, K. E., Leppla, S. H. & Moayeri, M. Anthrax lethal toxin-induced inflammasome formation and caspase-1 activation are late events dependent on ion fluxes and the proteasome. Cell. Microbiol. 10, 332–343 (2008).

    CAS  PubMed  Google Scholar 

  54. 54

    Fernandes-Alnemri, T. et al. The pyroptosome: a supramolecular assembly of ASC dimers mediating inflammatory cell death via caspase 1 activation. Cell Death Differ. 14, 1590–1604 (2007). This study found that a macromolecular structure which contained ASC and caspase-1 was formed during pyroptosis.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Miao, E. A. et al. Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1β via Ipaf. Nature Immunol. 7, 569–575 (2006).

    CAS  Google Scholar 

  56. 56

    Franchi, L. et al. Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1β in Salmonella-infected macrophages. Nature Immunol. 7, 576–582 (2006). Together with References 23 and 55, this study found that bacterial flagellin and the host protein NLRC4 are required for the activation of caspase 1 during infection with Legionella and Salmonella.

    CAS  Google Scholar 

  57. 57

    Zamboni, D. S. et al. The Birc1e cytosolic pattern-recognition receptor contributes to the detection and control of Legionella pneumophila infection. Nature Immunol. 7, 318–325 (2006).

    CAS  Google Scholar 

  58. 58

    Miao, E. A., Ernst, R. K., Dors, M., Mao, D. P. & Aderem, A. Pseudomonas aeruginosa activates caspase 1 through Ipaf. Proc. Natl Acad. Sci. USA 105, 2562–2567 (2008).

    CAS  PubMed  Google Scholar 

  59. 59

    Franchi, L. et al. Critical role for Ipaf in Pseudomonas aeruginosa-induced caspase-1 activation. Eur. J. Immunol. 37, 3030–3039 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Warren, S. E., Mao, D. P., Rodriguez, A. E., Miao, E. A. & Aderem, A. Multiple Nod-like receptors activate caspase 1 during Listeria monocytogenes infection. J. Immunol. 180, 7558–7564 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Lightfield, K. L. et al. Critical function for Naip5 in inflammasome activation by a conserved carboxy-terminal domain of flagellin. Nature Immunol. 9, 1171–1178 (2008).

    CAS  Google Scholar 

  62. 62

    Sutterwala, F. S. et al. Immune recognition of Pseudomonas aeruginosa mediated by the IPAF/NLRC4 inflammasome. J. Exp. Med. 204, 3235–3245 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Suzuki, T. et al. Differential regulation of caspase-1 activation, pyroptosis, and autophagy via Ipaf and ASC in Shigella-infected macrophages. PLoS Pathog. 3, e111 (2007).

    PubMed  PubMed Central  Google Scholar 

  64. 64

    Boyden, E. D. & Dietrich, W. F. Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin. Nature Genet. 38, 240–244 (2006).

    CAS  PubMed  Google Scholar 

  65. 65

    Martinon, F., Burns, K. & Tschopp, J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-β. Mol. Cell 10, 417–426 (2002). First description of the inflammasome as a caspase 1-activating platform.

    CAS  PubMed  Google Scholar 

  66. 66

    Faustin, B. et al. Reconstituted NALP1 inflammasome reveals two-step mechanism of caspase-1 activation. Mol. Cell 25, 713–724 (2007).

    CAS  PubMed  Google Scholar 

  67. 67

    Poyet, J. L. et al. Identification of Ipaf, a human caspase-1-activating protein related to Apaf-1. J. Biol. Chem. 276, 28309–28313 (2001).

    CAS  PubMed  Google Scholar 

  68. 68

    Mariathasan, S. et al. Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature 430, 213–218 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Schmidt, M., Hanna, J., Elsasser, S. & Finley, D. Proteasome-associated proteins: regulation of a proteolytic machine. Biol. Chem. 386, 725–737 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Bao, Q. & Shi, Y. Apoptosome: a platform for the activation of initiator caspases. Cell Death Differ. 14, 56–65 (2007).

    CAS  PubMed  Google Scholar 

  71. 71

    Amer, A. O. & Swanson, M. S. Autophagy is an immediate macrophage response to Legionella pneumophila. Cell. Microbiol. 7, 765–778 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    Swanson, M. S. & Molofsky, A. B. Autophagy and inflammatory cell death, partners of innate immunity. Autophagy 1, 174–176 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Checroun, C., Wehrly, T. D., Fischer, E. R., Hayes, S. F. & Celli, J. Autophagy-mediated reentry of Francisella tularensis into the endocytic compartment after cytoplasmic replication. Proc. Natl Acad. Sci. USA 103, 14578–14583 (2006).

    CAS  PubMed  Google Scholar 

  74. 74

    Willingham, S. B. et al. Microbial pathogen-induced necrotic cell death mediated by the inflammasome components CIAS1/cryopyrin/NLRP3 and ASC. Cell Host Microbe 2, 147–159 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Hernandez, L. D., Pypaert, M., Flavell, R. A. & Galan, J. E. A Salmonella protein causes macrophage cell death by inducing autophagy. J. Cell Biol. 163, 1123–1131 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Delaleu, N. & Bickel, M. Interleukin-1β and interleukin-18: regulation and activity in local inflammation. Periodontol. 2000 35, 42–52 (2004).

    PubMed  Google Scholar 

  77. 77

    Nakanishi, K., Yoshimoto, T., Tsutsui, H. & Okamura, H. Interleukin-18 regulates both Th1 and Th2 responses. Annu. Rev. Immunol. 19, 423–474 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Monack, D. M., Detweiler, C. S. & Falkow, S. Salmonella pathogenicity island 2-dependent macrophage death is mediated in part by the host cysteine protease caspase-1. Cell. Microbiol. 3, 825–837 (2001).

    CAS  PubMed  Google Scholar 

  79. 79

    Andrei, C. et al. The secretory route of the leaderless protein interleukin 1β involves exocytosis of endolysosome-related vesicles. Mol. Biol. Cell 10, 1463–1475 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Andrei, C. et al. Phospholipases C and A2 control lysosome-mediated IL-1β secretion: implications for inflammatory processes. Proc. Natl Acad. Sci. USA 101, 9745–9750 (2004).

    CAS  PubMed  Google Scholar 

  81. 81

    Brough, D. & Rothwell, N. J. Caspase-1-dependent processing of pro-interleukin-1β is cytosolic and precedes cell death. J. Cell Sci. 120, 772–781 (2007).

    CAS  PubMed  Google Scholar 

  82. 82

    Qu, Y., Franchi, L., Nunez, G. & Dubyak, G. R. Nonclassical IL-1β secretion stimulated by P2X7 receptors is dependent on inflammasome activation and correlated with exosome release in murine macrophages. J. Immunol. 179, 1913–1925 (2007).

    CAS  PubMed  Google Scholar 

  83. 83

    Pizzirani, C. et al. Stimulation of P2 receptors causes release of IL-1β-loaded microvesicles from human dendritic cells. Blood 109, 3856–3864 (2007).

    CAS  PubMed  Google Scholar 

  84. 84

    Bianco, F. et al. Astrocyte-derived ATP induces vesicle shedding and IL-1β release from microglia. J. Immunol. 174, 7268–7677 (2005).

    CAS  PubMed  Google Scholar 

  85. 85

    MacKenzie, A. et al. Rapid secretion of interleukin-1β by microvesicle shedding. Immunity 15, 825–835 (2001).

    CAS  PubMed  Google Scholar 

  86. 86

    Keller, M., Ruegg, A., Werner, S. & Beer, H. D. Active caspase-1 is a regulator of unconventional protein secretion. Cell 132, 818–831 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Miggin, S. M. et al. NF-κB activation by the Toll-IL-1 receptor domain protein MyD88 adapter-like is regulated by caspase-1. Proc. Natl Acad. Sci. USA 104, 3372–3377 (2007).

    CAS  PubMed  Google Scholar 

  88. 88

    Amer, A. et al. Regulation of Legionella phagosome maturation and infection through flagellin and host Ipaf. J. Biol. Chem. 281, 35217–35223 (2006).

    CAS  PubMed  Google Scholar 

  89. 89

    Master, S. S. et al. Mycobacterium tuberculosis prevents inflammasome activation. Cell Host Microbe 3, 224–232 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Siegel, R. M. Caspases at the crossroads of immune-cell life and death. Nature Rev. Immunol. 6, 308–317 (2006).

    CAS  Google Scholar 

  91. 91

    Shin, H. & Cornelis, G. R. Type III secretion translocation pores of Yersinia enterocolitica trigger maturation and release of pro-inflammatory IL-1β. Cell. Microbiol. 9, 2893–2902 (2007).

    CAS  PubMed  Google Scholar 

  92. 92

    Simon, A. & van der Meer, J. W. Pathogenesis of familial periodic fever syndromes or hereditary autoinflammatory syndromes. Am. J. Physiol. Regul. Integr. Comp. Physiol. 292, R86–R98 (2007).

    CAS  PubMed  Google Scholar 

  93. 93

    Schielke, G. P., Yang, G. Y., Shivers, B. D. & Betz, A. L. Reduced ischemic brain injury in interleukin-1β converting enzyme-deficient mice. J. Cereb. Blood Flow Metab. 18, 180–185 (1998).

    CAS  PubMed  Google Scholar 

  94. 94

    Siegmund, B., Lehr, H. A., Fantuzzi, G. & Dinarello, C. A. IL-1β-converting enzyme (caspase-1) in intestinal inflammation. Proc. Natl Acad. Sci. USA 98, 13249–13254 (2001).

    CAS  PubMed  Google Scholar 

  95. 95

    Ona, V. O. et al. Inhibition of caspase-1 slows disease progression in a mouse model of Huntington's disease. Nature 399, 263–267 (1999).

    CAS  PubMed  Google Scholar 

  96. 96

    Wang, W. et al. Endotoxemic acute renal failure is attenuated in caspase-1-deficient mice. Am. J. Physiol. Renal Physiol. 288, F997–F1004 (2005).

    CAS  PubMed  Google Scholar 

  97. 97

    Faubel, S. et al. Cisplatin-induced acute renal failure is associated with an increase in the cytokines interleukin (IL)-1, IL-18, IL-6, and neutrophil infiltration in the kidney. J. Pharmacol. Exp. Ther. 322, 8–15 (2007).

    CAS  PubMed  Google Scholar 

  98. 98

    Sarkar, A. et al. Caspase-1 regulates Escherichia coli sepsis and splenic B cell apoptosis independently of interleukin-1β and interleukin-18. Am. J. Respir. Crit. Care Med. 174, 1003–1010 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    Lara-Tejero, M. et al. Role of the caspase-1 inflammasome in Salmonella typhimurium pathogenesis. J. Exp. Med. 203, 1407–1412 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    Raupach, B., Peuschel, S. K., Monack, D. M. & Zychlinsky, A. Caspase-1-mediated activation of interleukin-1β (IL-1β) and IL-18 contributes to innate immune defenses against Salmonella enterica serovar Typhimurium infection. Infect. Immun. 74, 4922–4926 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    Sansonetti, P. J. et al. Caspase-1 activation of IL-1β and IL-18 are essential for Shigella flexneri-induced inflammation. Immunity 12, 581–590 (2000).

    CAS  PubMed  Google Scholar 

  102. 102

    Pedra, J. H. et al. ASC/PYCARD and caspase-1 regulate the IL-18/IFN-γ axis during Anaplasma phagocytophilum infection. J. Immunol. 179, 4783–4791 (2007).

    CAS  PubMed  Google Scholar 

  103. 103

    Tsuji, N. M. et al. Roles of caspase-1 in Listeria infection in mice. Int. Immunol. 16, 335–343 (2004).

    CAS  PubMed  Google Scholar 

  104. 104

    Henry, T. & Monack, D. M. Activation of the inflammasome upon Francisella tularensis infection: interplay of innate immune pathways and virulence factors. Cell Microbiol. 9, 2543–2551 (2007). Identified a role for type I IFN signalling in priming macrophages to undergo pyroptosis in response to Francisella infection.

    CAS  PubMed  Google Scholar 

  105. 105

    Mencacci, A. et al. Interleukin 18 restores defective Th1 immunity to Candida albicans in caspase 1-deficient mice. Infect. Immun. 68, 5126–5131 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106

    Shi, Y., Evans, J. E. & Rock, K. L. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 425, 516–521 (2003).

    CAS  PubMed  Google Scholar 

  107. 107

    Mariathasan, S. & Monack, D. M. Inflammasome adaptors and sensors: intracellular regulators of infection and inflammation. Nature Rev. Immunol. 7, 31–40 (2007).

    CAS  Google Scholar 

  108. 108

    Kool, M. et al. Alum adjuvant boosts adaptive immunity by inducing uric acid and activating inflammatory dendritic cells. J. Exp. Med. 205, 869–882 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109

    Kool, M. et al. Cutting edge: alum adjuvant stimulates inflammatory dendritic cells through activation of the NALP3 inflammasome. J. Immunol. 181, 3755–3759 (2008).

    CAS  PubMed  Google Scholar 

  110. 110

    Eisenbarth, S. C., Colegio, O. R., O'Connor, W., Sutterwala, F. S. & Flavell, R. A. Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature 453, 1122–1126 (2008). Showed that the adjuvant activity of alum is due to its ability to stimulate caspase 1 activation, highlighting the role of caspase 1 in the enhancement of adaptive immunity.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111

    Franchi, L. & Nunez, G. The Nlrp3 inflammasome is critical for aluminium hydroxide-mediated IL-1β secretion but dispensable for adjuvant activity. Eur. J. Immunol. 38, 2085–2089 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112

    Li, H., Willingham, S. B., Ting, J. P. & Re, F. Cutting edge: inflammasome activation by alum and alum's adjuvant effect are mediated by NLRP3. J. Immunol. 181, 17–21 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113

    Lockman, H. A. & Curtiss, R. 3rd. Salmonella typhimurium mutants lacking flagella or motility remain virulent in BALB/c mice. Infect. Immun. 58, 137–143 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114

    Hammer, B. K. & Swanson, M. S. Co-ordination of Legionella pneumophila virulence with entry into stationary phase by ppGpp. Mol. Microbiol. 33, 721–731 (1999).

    CAS  PubMed  Google Scholar 

  115. 115

    Cummings, L. A., Barrett, S. L., Wilkerson, W. D., Fellnerova, I. & Cookson, B. T. FliC-specific CD4+ T cell responses are restricted by bacterial regulation of antigen expression. J. Immunol. 174, 7929–7938 (2005).

    CAS  PubMed  Google Scholar 

  116. 116

    Johnston, J. B. et al. A poxvirus-encoded pyrin domain protein interacts with ASC-1 to inhibit host inflammatory and apoptotic responses to infection. Immunity 23, 587–598 (2005). This study identified a microbial protein that is capable of inhibiting caspase 1 activation by disrupting inflammasome formation.

    CAS  PubMed  Google Scholar 

  117. 117

    Stasakova, J. et al. Influenza A mutant viruses with altered NS1 protein function provoke caspase-1 activation in primary human macrophages, resulting in fast apoptosis and release of high levels of interleukins 1β and 18. J. Gen. Virol. 86, 185–195 (2005).

    CAS  PubMed  Google Scholar 

  118. 118

    Schotte, P. et al. Targeting Rac1 by the Yersinia effector protein YopE inhibits caspase-1-mediated maturation and release of interleukin-1β. J. Biol. Chem. 279, 25134–25142 (2004).

    CAS  PubMed  Google Scholar 

  119. 119

    Weiss, D. S. et al. In vivo negative selection screen identifies genes required for Francisella virulence. Proc. Natl Acad. Sci. USA 104, 6037–6042 (2007).

    CAS  PubMed  Google Scholar 

  120. 120

    Henry, T., Brotcke, A., Weiss, D. S., Thompson, L. J. & Monack, D. M. Type I interferon signaling is required for activation of the inflammasome during Francisella infection. J. Exp. Med. 204, 987–994 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121

    Esposti, M. D. Apoptosis: who was first? Cell Death Differ. 5, 719 (1998).

    CAS  PubMed  Google Scholar 

  122. 122

    Kerr, J. F., Wyllie, A. H. & Currie, A. R. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer 26, 239–257 (1972).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123

    Majno, G. & Joris, I. Apoptosis, oncosis, and necrosis. An overview of cell death. Am. J. Pathol. 146, 3–15 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124

    Fernandez-Prada, C. M., Hoover, D. L., Tall, B. D. & Venkatesan, M. M. Human monocyte-derived macrophages infected with virulent Shigella flexneri in vitro undergo a rapid cytolytic event similar to oncosis but not apoptosis. Infect. Immun. 65, 1486–1496 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

S.L.F. was supported by National Institutes of Health Grants AI47242 and P50 HG02360 and Poncin and Achievement Rewards for College Scientist Fellowships. T.B. was supported by National Institute of General Medical Sciences Public Health Service National Research Service Award Grant T32 GM07270 and a Helen Riaboff Whitely Fellowship.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Brad T. Cookson.

Related links

Related links

DATABASES

Entrez Genome Project

Anaplasma phagocytophilum

Bacillus anthracis

Candida albicans

Mycobacterium tuberculosis

FURTHER INFORMATION

Brad T. Cookson's homepage

Glossary

Caspases

A group of cysteine proteases that, based on their physiological roles, can be divided into two groups: those involved in the initiation and execution of apoptosis (caspase 2, 3, 6, 7, 8, 9 and 10) and those that trigger inflammation (caspase 1 and related caspases).

Autophagy

A programme of cellular self-digestion in which cytoplasmic components are sequestered and degraded intracellularly in autophagosomes. Autophagic cell corpses are ultimately removed by phagocytosis.

Oncosis

A caspase-independent pathway of cell death triggered by exposure to toxins or physical damage that features organelle and cell swelling and culminates in cell lysis with release of intracellular contents that stimulate inflammatory responses.

Toll-like receptor

A transmembrane protein that contains a leucine-rich repeat domain and mediates host recognition of pathogen- and danger-associated molecular patterns located in the extracellular milieu or within endosomes.

Nod-like receptor

A protein that contains a leucine-rich repeat domain and mediates host recognition of pathogen- and danger-associated molecular patterns in the host cell cytosol.

Proteasome

A multiprotein complex that recognizes and degrades polyubiquitinated substrates.

Pyronecrosis

Results from Shigella infection at high MOI (multiplicity of infection), morphologically resembles oncosis and is NLRP3-dependent and caspase 1-independent.

Microvesicle

A membrane vesicle of less than 0.5 μm in diameter that is shed from the plasma membrane of eukaryotic cells.

Necrosis

Does not indicate a specific pathway of cell death, but is a post-mortem description of dead cells that have reached equilibrium with their surroundings.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Bergsbaken, T., Fink, S. & Cookson, B. Pyroptosis: host cell death and inflammation. Nat Rev Microbiol 7, 99–109 (2009). https://doi.org/10.1038/nrmicro2070

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing