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.

  • Review Article
  • Published:

Emerging inflammasome effector mechanisms

Nature Reviews Immunology volume 11, pages 213–220 (2011)Cite this article

Subjects

Key Points

  • In addition to mediating the maturation and secretion of the cytokines interleukin-1β (IL-1β) and IL-18, caspase 1 activation by inflammasome complexes controls a set of non-canonical effectors that might contribute to the immune response during infection and autoimmunity. These mechanisms include unconventional protein secretion, pyroptosis, regulation of metabolic pathways and restriction of bacterial replication.

  • Caspase 1 activation in macrophages, epithelial cells and keratinocytes drives unconventional protein secretion of leaderless cytokines such as IL-1α, IL-1β and IL-18, growth factors such as fibroblast growth factor 2 and possibly damage-associated molecular patterns such as high mobility group box 1. After their release into the extracellular environment, these factors can enhance inflammatory and healing responses.

  • Infected myeloid cells can remove intracellular replication niches for pathogens by inducing pyroptosis, a specialized caspase 1-dependent cell death programme. Pyroptosis is accompanied by osmotic lysis and the release of the intracellular content into the extracellular milieu, and this is thought (together with other inflammasome functions) to render it an inherently pro-inflammatory cell death mode. Pyroptosis is thought to confer resistance to infection with intracellular pathogens in vivo, illustrating the importance of this cell death mode for host defence.

  • Caspase 1 can cleave poly(ADP-ribose) polymerase 1 (PARP1) and glycolysis enzymes (such as glyceraldehyde-3-phosphate dehydrogenase) to preserve ATP energy stores and to decrease the metabolic rate of infected cells. As such, caspase 1-mediated targeting of bioenergetic pathways might help to preserve cellular energy stores during infection.

  • Caspase 1 activates lipid metabolic pathways in fibroblasts intoxicated with pore-forming toxins or infected with bacteria that produce these toxins. This leads to the repair of toxin-induced damage to the plasma membrane and promotes cell survival.

  • In a process that proceeds independently of IL-1β and IL-18, caspase 1-mediated activation of caspase 7, an executioner caspase, contributes to the restriction of Legionella pneumophila replication in infected macrophages. In vivo studies have shown the importance of this inflammasome pathway for host defence against L. pneumophila infection in the lungs.

Abstract

Caspase 1 activation by inflammasome complexes in response to pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) induces the maturation and secretion of the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18. Recent reports have begun to identify additional inflammasome effector mechanisms that proceed independently of IL-1β and IL-18. These include the induction of pyroptotic cell death, the restriction of bacterial replication, the activation of lipid metabolic pathways for cell repair and the secretion of DAMPs and leaderless cytokines. These non-canonical functions of caspase 1 illustrate the diverse mechanisms by which inflammasomes might contribute to innate immunity, repair responses and host defence.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Inflammasomes: composition and stimuli.
Figure 2: Main features of pyroptosis.
Figure 3: Caspase 1 effector mechanisms.

Similar content being viewed by others

References

  1. Villani, A. C. et al. Common variants in the NLRP3 region contribute to Crohn's disease susceptibility. Nature Genet. 41, 71–76 (2009).

    Article  CAS  PubMed  Google Scholar 

  2. Zaki, M. H. et al. The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis. Immunity 32, 379–391 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Allen, I. C. et al. The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer. J. Exp. Med. 207, 1045–1056 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bauer, C. et al. Colitis induced in mice with dextran sulfate sodium (DSS) is mediated by the NLRP3 inflammasome. Gut 59, 1192–1199 (2010).

    Article  CAS  PubMed  Google Scholar 

  5. Dupaul-Chicoine, J. et al. Control of intestinal homeostasis, colitis, and colitis-associated colorectal cancer by the inflammatory caspases. Immunity 32, 367–378 (2010).

    Article  CAS  PubMed  Google Scholar 

  6. Jin, Y. et al. NALP1 in vitiligo-associated multiple autoimmune disease. N. Engl. J. Med. 356, 1216–1225 (2007).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  8. Magitta, N. F. et al. A coding polymorphism in NALP1 confers risk for autoimmune Addison's disease and type 1 diabetes. Genes Immun. 10, 120–124 (2009).

    Article  CAS  PubMed  Google Scholar 

  9. Larsen, C. M. et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N. Engl. J. Med. 356, 1517–1526 (2007).

    Article  CAS  PubMed  Google Scholar 

  10. Agostini, L. et al. NALP3 forms an IL-1β-processing inflammasome with increased activity in Muckle–Wells autoinflammatory disorder. Immunity 20, 319–325 (2004).

    Article  CAS  PubMed  Google Scholar 

  11. Hoffman, H. M., Mueller, J. L., Broide, D. H., Wanderer, A. A. & Kolodner, R. D. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle–Wells syndrome. Nature Genet. 29, 301–305 (2001).

    Article  CAS  PubMed  Google Scholar 

  12. Lamkanfi, M. & Dixit, V. M. The inflammasomes. PLoS Pathog. 5, e1000510 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kawai, T. & Akira, S. TLR signaling. Cell Death Differ. 13, 816–825 (2006).

    Article  CAS  PubMed  Google Scholar 

  14. Tschopp, J. & Schroder, K. NLRP3 inflammasome activation: the convergence of multiple signalling pathways on ROS production? Nature Rev. Immunol. 10, 210–215 (2010).

    Article  CAS  Google Scholar 

  15. Lamkanfi, M. & Dixit, V. M. Inflammasomes: guardians of cytosolic sanctity. Immunol. Rev. 227, 95–105 (2009).

    Article  CAS  PubMed  Google Scholar 

  16. Gu, Y. et al. Activation of interferon-γ inducing factor mediated by interleukin-1β converting enzyme. Science 275, 206–209 (1997).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  18. Ghayur, T. et al. Caspase-1 processes IFN-γ-inducing factor and regulates LPS-induced IFN-γ production. Nature 386, 619–623 (1997).

    Article  CAS  PubMed  Google Scholar 

  19. 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).

    Article  CAS  PubMed  Google Scholar 

  20. Joosten, L. A. et al. Inflammatory arthritis in caspase 1 gene-deficient mice: contribution of proteinase 3 to caspase 1-independent production of bioactive interleukin-1β. Arthritis Rheum. 60, 3651–3662 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Irmler, M. et al. Granzyme A is an interleukin 1β-converting enzyme. J. Exp. Med. 181, 1917–1922 (1995).

    Article  CAS  PubMed  Google Scholar 

  22. Maelfait, J. et al. Stimulation of Toll-like receptor 3 and 4 induces interleukin-1β maturation by caspase-8. J. Exp. Med. 205, 1967–1973 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Mayer-Barber, K. D. et al. Caspase-1 independent IL-1β production is critical for host resistance to Mycobacterium tuberculosis and does not require TLR signaling in vivo. J. Immunol. 184, 3326–3330 (2010).

    Article  CAS  PubMed  Google Scholar 

  24. Kanneganti, T. D. Central roles of NLRs and inflammasomes in viral infection. Nature Rev. Immunol. 10, 688–698 (2010).

    Article  CAS  Google Scholar 

  25. Sims, J. E. & Smith, D. E. The IL-1 family: regulators of immunity. Nature Rev. Immunol. 10, 89–102 (2010).

    Article  CAS  Google Scholar 

  26. Dinarello, C. A. Immunological and inflammatory functions of the interleukin-1 family. Annu. Rev. Immunol. 27, 519–550 (2009).

    Article  CAS  PubMed  Google Scholar 

  27. Hoshino, T. et al. Cutting edge: IL-18-transgenic mice: in vivo evidence of a broad role for IL-18 in modulating immune function. J. Immunol. 166, 7014–7018 (2001).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  29. Weaver, C. T., Harrington, L. E., Mangan, P. R., Gavrieli, M. & Murphy, K. M. Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 24, 677–688 (2006).

    Article  CAS  PubMed  Google Scholar 

  30. Harrington, L. E. et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nature Immunol. 6, 1123–1132 (2005).

    Article  CAS  Google Scholar 

  31. Hoffman, H. M. et al. Efficacy and safety of rilonacept (interleukin-1 trap) in patients with cryopyrin-associated periodic syndromes: results from two sequential placebo-controlled studies. Arthritis Rheum. 58, 2443–2452 (2008).

    Article  CAS  PubMed  Google Scholar 

  32. Lachmann, H. J. et al. Use of canakinumab in the cryopyrin-associated periodic syndrome. N. Engl. J. Med. 360, 2416–2425 (2009).

    Article  CAS  PubMed  Google Scholar 

  33. Lamkanfi, M. et al. Inflammasome-dependent release of the alarmin HMGB1 in endotoxemia. J. Immunol. 185, 4385–4392 (2010). This paper describes the role of the NLRP3 and NLRC4 inflammasomes in extracellular release of HMGB1.

    Article  CAS  PubMed  Google Scholar 

  34. Miao, E. A. et al. Caspase-1-induced pyroptosis is an innate immune effector mechanism against intracellular bacteria. Nature Immunol. 11, 1136–1142 (2010). This paper describes the crucial role of caspase 1-mediated cell death as a host defence mechanism against bacterial pathogens.

    Article  CAS  Google Scholar 

  35. 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). This paper describes the increased susceptibility of caspase 1-deficient mice to infection with Francisella tularensis compared with mice lacking IL-1β and IL-18.

    Article  CAS  PubMed  Google Scholar 

  36. Trombetta, E. S. & Parodi, A. J. Quality control and protein folding in the secretory pathway. Annu. Rev. Cell. Dev. Biol. 19, 649–676 (2003).

    Article  CAS  PubMed  Google Scholar 

  37. Lee, M. C., Miller, E. A., Goldberg, J., Orci, L. & Schekman, R. Bi-directional protein transport between the ER and Golgi. Annu. Rev. Cell. Dev. Biol. 20, 87–123 (2004).

    Article  CAS  PubMed  Google Scholar 

  38. Nickel, W. & Rabouille, C. Mechanisms of regulated unconventional protein secretion. Nature Rev. Mol. Cell Biol. 10, 148–155 (2009).

    Article  CAS  Google Scholar 

  39. Rubartelli, A., Cozzolino, F., Talio, M. & Sitia, R. A novel secretory pathway for interleukin-1β, a protein lacking a signal sequence. EMBO J. 9, 1503–1510 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sutterwala, F. S. et al. Critical role for NALP3/CIAS1/Cryopyrin in innate and adaptive immunity through its regulation of caspase-1. Immunity 24, 317–327 (2006).

    Article  CAS  PubMed  Google Scholar 

  41. Keller, M., Ruegg, A., Werner, S. & Beer, H. D. Active caspase-1 is a regulator of unconventional protein secretion. Cell 132, 818–831 (2008). This paper characterizes the role of caspase 1 in the secretion of IL-1α and FGF2.

    Article  CAS  PubMed  Google Scholar 

  42. Becker, C. E., Creagh, E. M. & O'Neill, L. A. Rab39a binds caspase-1 and is required for caspase-1-dependent interleukin-1β secretion. J. Biol. Chem. 284, 34531–34537 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Salvesen, G. S. & Riedl, S. J. Caspase mechanisms. Adv. Exp. Med. Biol. 615, 13–23 (2008).

    Article  CAS  PubMed  Google Scholar 

  44. Riedl, S. J. & Shi, Y. Molecular mechanisms of caspase regulation during apoptosis. Nature Rev. Mol. Cell Biol. 5, 897–907 (2004).

    Article  CAS  Google Scholar 

  45. Lamkanfi, M. & Dixit, V. M. Manipulation of host cell death pathways during microbial infections. Cell Host Microbe 8, 44–54 (2010).

    Article  CAS  PubMed  Google Scholar 

  46. Strasser, A., O'Connor, L. & Dixit, V. M. Apoptosis signaling. Annu. Rev. Biochem. 69, 217–245 (2000).

    Article  CAS  PubMed  Google Scholar 

  47. Taylor, R. C., Cullen, S. P. & Martin, S. J. Apoptosis: controlled demolition at the cellular level. Nature Rev. Mol. Cell Biol. 9, 231–241 (2008).

    Article  CAS  Google Scholar 

  48. Kazama, H. et al. Induction of immunological tolerance by apoptotic cells requires caspase-dependent oxidation of high-mobility group box-1 protein. Immunity 29, 21–32 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Savill, J., Dransfield, I., Gregory, C. & Haslett, C. A blast from the past: clearance of apoptotic cells regulates immune responses. Nature Rev. Immunol. 2, 965–975 (2002).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  51. Lamkanfi, M. et al. Targeted peptidecentric proteomics reveals caspase-7 as a substrate of the caspase-1 inflammasomes. Mol. Cell. Proteomics 7, 2350–2363 (2008). This paper describes caspase 7 as a downstream effector of the NLRP3 and NLRC4 inflammasomes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. 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).

    Article  CAS  PubMed  Google Scholar 

  53. Lamkanfi, M. et al. Glyburide inhibits the Cryopyrin/Nalp3 inflammasome. J. Cell Biol. 187, 61–70 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  56. 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). This paper reports that pyroptosis proceeds independently of IL-1β and IL-18.

    Article  CAS  PubMed  Google Scholar 

  57. 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).

    Article  CAS  PubMed  Google Scholar 

  58. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

  60. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  62. Miao, E. A. et al. Innate immune detection of the type III secretion apparatus through the NLRC4 inflammasome. Proc. Natl Acad. Sci. USA 107, 3076–3080 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  65. Terra, J. K. et al. Cutting edge: resistance to Bacillus anthracis infection mediated by a lethal toxin sensitive allele of Nalp1b/Nlrp1b. J. Immunol. 184, 17–20 (2010).

    Article  CAS  PubMed  Google Scholar 

  66. Munoz-Planillo, R., Franchi, L., Miller, L. S. & Nunez, G. A critical role for hemolysins and bacterial lipoproteins in Staphylococcus aureus-induced activation of the Nlrp3 inflammasome. J. Immunol. 183, 3942–3948 (2009).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  68. Sauer, J. D. et al. Listeria monocytogenes triggers AIM2-mediated pyroptosis upon infrequent bacteriolysis in the macrophage cytosol. Cell Host Microbe 7, 412–419 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Fernandes-Alnemri, T. et al. The AIM2 inflammasome is critical for innate immunity to Francisella tularensis. Nature Immunol. 11, 385–393 (2010).

    Article  CAS  Google Scholar 

  70. Rathinam, V. A. et al. The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses. Nature Immunol. 11, 395–402 (2010).

    Article  CAS  Google Scholar 

  71. Jones, J. W. et al. Absent in melanoma 2 is required for innate immune recognition of Francisella tularensis. Proc. Natl Acad. Sci. USA 107, 9771–9776 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Wu, J., Fernandes-Alnemri, T. & Alnemri, E. S. Involvement of the AIM2, NLRC4, and NLRP3 inflammasomes in caspase-1 activation by Listeria monocytogenes. J. Clin. Immunol. 30, 693–702 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Warren, S. E. et al. Cutting edge: cytosolic bacterial DNA activates the inflammasome via Aim2. J. Immunol. 185, 818–821 (2010).

    Article  CAS  PubMed  Google Scholar 

  74. Tsuchiya, K. et al. Involvement of absent in melanoma 2 in inflammasome activation in macrophages infected with Listeria monocytogenes. J. Immunol. 185, 1186–1195 (2010).

    Article  CAS  PubMed  Google Scholar 

  75. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. 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).

    Article  CAS  PubMed  Google Scholar 

  78. Malireddi, R. K., Ippagunta, S., Lamkanfi, M. & Kanneganti, T. D. Cutting edge: proteolytic inactivation of poly(ADP-ribose) polymerase 1 by the Nlrp3 and Nlrc4 inflammasomes. J. Immunol. 185, 3127–3130 (2010). This paper describes the inflammasome-dependent cleavage of PARP1 during pyroptosis.

    Article  CAS  PubMed  Google Scholar 

  79. Akhter, A. et al. Caspase-7 activation by the Nlrc4/Ipaf inflammasome restricts Legionella pneumophila infection. PLoS Pathog. 5, e1000361 (2009). This paper describes the role of caspase 7 activation by the NLRC4 inflammasome in restricting Legionella replication.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Lakhani, S. A. et al. Caspases 3 and 7: key mediators of mitochondrial events of apoptosis. Science 311, 847–851 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. 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). This paper describes glycolysis enzymes as substrates of caspase 1.

    Article  CAS  PubMed  Google Scholar 

  82. Cramer, T. et al. HIF-1α is essential for myeloid cell-mediated inflammation. Cell 112, 645–657 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. 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). This paper reports that inflammasomes activate lipid metabolic pathways.

    Article  CAS  PubMed  Google Scholar 

  84. Gonzalez, M. R., Bischofberger, M., Pernot, L., van der Goot, F. G. & Freche, B. Bacterial pore-forming toxins: the (w)hole story? Cell. Mol. Life Sci. 65, 493–507 (2008).

    Article  CAS  PubMed  Google Scholar 

  85. McCoy, A. J. et al. Cytotoxins of the human pathogen Aeromonas hydrophila trigger, via the NLRP3 inflammasome, caspase-1 activation in macrophages. Eur. J. Immunol. 40, 2797–2803 (2010).

    Article  CAS  PubMed  Google Scholar 

  86. Lamkanfi, M. et al. The Nod-like receptor family member Naip5/Birc1e restricts Legionella pneumophila growth independently of caspase-1 activation. J. Immunol. 178, 8022–8027 (2007).

    Article  CAS  PubMed  Google Scholar 

  87. 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).

    Article  CAS  Google Scholar 

  88. Broz, P. et al. Redundant roles for inflammasome receptors NLRP3 and NLRC4 in host defense against Salmonella. J. Exp. Med. 207, 1745–1755 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Fischer, U., Janicke, R. U. & Schulze-Osthoff, K. Many cuts to ruin: a comprehensive update of caspase substrates. Cell Death Differ. 10, 76–100 (2003).

    Article  CAS  PubMed  Google Scholar 

  90. Lamkanfi, M., Festjens, N., Declercq, W., Vanden Berghe, T. & Vandenabeele, P. Caspases in cell survival, proliferation and differentiation. Cell Death Differ. 14, 44–55 (2007).

    Article  CAS  PubMed  Google Scholar 

  91. Boatright, K. M. et al. A unified model for apical caspase activation. Mol. Cell 11, 529–541 (2003).

    Article  CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by European Union Framework Program 7 (Marie Curie grant 256432) and by the Fund for Scientific Research – Flanders.

Author information

Authors and Affiliations

  1. Department of Biochemistry, and VIB Department of Medical Protein Research, Ghent University, Albert Baertsoenkaai 3, B-9000, Ghent, Belgium

    Mohamed Lamkanfi

Authors
  1. Mohamed Lamkanfi
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

The author declares no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Mohamed Lamkanfi's homepage

Glossary

Cryopyrinopathies

A spectrum of hereditary autoinflammatory diseases that are caused by mutations in the gene encoding NLR family, pyrin domain-containing 3 (NLRP3) that trigger continuous activation of the NLRP3 inflammasome. Based on the severity and spectrum of the symptoms — which can include urticarial skin rashes, prolonged episodes of fever, sensorineural hearing loss, headaches, cognitive deficits and renal amyloidosis — these diseases are classified as familial cold autoinflammatory syndrome, Muckle–Wells syndrome or chronic infantile neurological cutaneous articular syndrome.

Proximity-induced autoactivation

A process in which two or more initiator caspases are brought sufficiently close to induce their autocatalytic activation. This process is thought to occur in large cytosolic protein complexes to which caspase zymogens are recruited by means of homotypic interactions between the caspase recruitment domain (CARD) or death effector domain (DED) motifs in their pro-domains and several bipartite adaptor molecules.

NOD-like receptor

(NLR). The human NLR family comprises 22 members. They share a domain organization that usually includes an amino-terminal caspase recruitment domain (CARD) or pyrin domain (PYD), followed by an intermediary nucleotide-binding oligomerization domain (NOD) and carboxy-terminal leucine-rich repeat motifs. NLRs are thought to survey the host cytosol and intracellular compartments for pathogen- and damage-associated molecular patterns to activate signalling pathways that contribute to the host innate immune response.

Pathogen-associated molecular pattern

(PAMP). A conserved pathogen molecule that is usually essential for microbial survival, and that contains either nucleic acid structures that are unique to microorganisms or cell wall components (such as lipopolysaccharide and flagellin) that are not found in mammalian cells. PAMPs are ligands for receptors of the host innate immune system.

Damage-associated molecular pattern

(DAMP). A molecule that is produced or released from host cells upon cellular stress, damage or non-physiological cell death. DAMPs are also referred to as 'alarmins' and are thought to be responsible for the initiation and perpetuation of inflammatory responses and tissue repair under non-infectious (sterile) conditions. Examples include high-mobility group box 1 (HMGB1), ATP, uric acid and heat-shock proteins.

Unconventional protein secretion

The secretion of cytoplasmic and nuclear proteins into the extracellular space through an incompletely understood mechanism that does not require the translocation apparatus of the classical endoplasmic reticulum (ER)–Golgi secretion pathway. Proteins that are secreted through this route include interleukin-1α (IL-1α), IL-1β, IL-18, fibroblast growth factor 2, galectin 1, galectin 3 and possibly high-mobility group box 1.

Pyroptosis

A specialized form of programmed cell death that requires caspase 1 activity. It is characterized by cytoplasmic swelling, early plasma membrane rupture, nuclear condensation and internucleosomal DNA fragmentation. The cytoplasmic content is released into the extracellular space, and this is thought to augment inflammatory and repair responses. Pyroptosis occurs in myeloid cells infected with pathogenic bacteria, and it might affect cells of the central nervous system and the cardiovascular system under ischaemic conditions.

Type III and type IV secretion

Two of at least six specialized secretion systems by which Gram-negative pathogens can deliver virulence factors into eukaryotic host cells. Pathogenic bacteria such as Shigella, Salmonella, Yersinia, Chlamydia and Pseudomonas spp. all make use of a type III secretion system to infect host cells and to modulate signalling pathways. By contrast, pathogens such as Helicobacter pylori, Legionella pneumophila and Bordetella pertussis make use of a type IV secretion system for the horizontal transfer of plasmid DNA containing antibiotic resistance genes and to inject effector proteins into eukaryotic host cells.

Glycolysis

A metabolic pathway that generates the cellular high-energy store ATP by oxidizing glucose to pyruvate. In eukaryotic cells, pyruvate is further oxidized into CO2 and H2O in a process known as 'aerobic respiration'. This results in a net yield of 36–38 molecules of ATP per metabolized molecule of glucose.

Autophagosome

A double-membrane-bound vesicle that is used by eukaryotic cells to target protein aggregates, damaged organelles and invading microorganisms for digestion by lysosomal hydrolases. This catabolic process allows recycling of cellular components and is thought to contribute to cell death, cell survival during starvation, cellular differentiation and host defence against infectious agents.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lamkanfi, M. Emerging inflammasome effector mechanisms. Nat Rev Immunol 11, 213–220 (2011). https://doi.org/10.1038/nri2936

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri2936

This article is cited by

Search

Advanced 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