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:

Inflammasomes in the CNS

Nature Reviews Neuroscience volume 15, pages 84–97 (2014)Cite this article

Subjects

Key Points

  • 'Inflammasomes' are intracellular protein complexes, which function as sensors for infectious or injurious stimuli and enable innate immune responses. They are increasingly being recognized as determinants of CNS diseases.

  • Inflammasome aggregation and activation result in the maturation and extracellular release of the cytokines interleukin-1β (IL-1β) and IL-18, largely from mononuclear phagocytic cells of the CNS such as microglia, but inflammasome formation in neurons is being increasingly appreciated.

  • Inflammasome activation, particularly the NOD-, LRR- and pyrin domain-containing 3 (NLPR3) inflammasome, has been reported across a broad spectrum of CNS diseases, including acute bacterial or viral infections, sterile injuries such as stroke and in chronic diseases such as Alzheimer's disease and multiple sclerosis.

Abstract

Microglia and macrophages in the CNS contain multimolecular complexes termed inflammasomes. Inflammasomes function as intracellular sensors for infectious agents as well as for host-derived danger signals that are associated with neurological diseases, including meningitis, stroke and Alzheimer's disease. Assembly of an inflammasome activates caspase 1 and, subsequently, the proteolysis and release of the cytokines interleukin-1β and interleukin-18, as well as pyroptotic cell death. Since the discovery of inflammasomes in 2002, there has been burgeoning recognition of their complexities and functions. Here, we review the current understanding of the functions of different inflammasomes in the CNS and their roles in neurological diseases.

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: Inflammasome activation.
Figure 2: Inflammasome components and domain structure.
Figure 3: Location and identity of inflammasome complexes implicated in neurological conditions.

Similar content being viewed by others

References

  1. Ransohoff, R. M. & Brown, M. A. Innate immunity in the central nervous system. J. Clin. Invest. 122, 1164–1171 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Glass, C. K., Saijo, K., Winner, B., Marchetto, M. C. & Gage, F. H. Mechanisms underlying inflammation in neurodegeneration. Cell 140, 918–934 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Allan, S. M. & Rothwell, N. J. Cytokines and acute neurodegeneration. Nature Rev. Neurosci. 2, 734–744 (2001).

    Article  CAS  Google Scholar 

  4. 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). This article coined the term 'inflammasome' and described the complex for the first time.

    Article  CAS  PubMed  Google Scholar 

  5. Rathinam, V. A., Vanaja, S. K. & Fitzgerald, K. A. Regulation of inflammasome signaling. Nature Immunol. 13, 333–342 (2012).

    Article  CAS  Google Scholar 

  6. 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 

  7. Minkiewicz, J., de Rivero Vaccari, J. P. & Keane, R. W. Human astrocytes express a novel NLRP2 inflammasome. Glia 61, 1113–1121 (2013).

    Article  PubMed  Google Scholar 

  8. Fernandes-Alnemri, T., Yu, J. W., Datta, P., Wu, J. & Alnemri, E. S. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature 458, 509–513 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  10. Case, C. L. & Roy, C. R. Asc modulates the function of NLRC4 in response to infection of macrophages by Legionella pneumophila. mBio 2, e00117-11 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Franchi, L., Munoz-Planillo, R. & Nunez, G. Sensing and reacting to microbes through the inflammasomes. Nature Immunol. 13, 325–332 (2012).

    Article  CAS  Google Scholar 

  12. Allan, S. M., Tyrrell, P. J. & Rothwell, N. J. Interleukin-1 and neuronal injury. Nature Rev. Immunol. 5, 629–640 (2005).

    Article  CAS  Google Scholar 

  13. Alboni, S., Cervia, D., Sugama, S. & Conti, B. Interleukin 18 in the CNS. J. Neuroinflammation 7, 9 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. John, G. R., Lee, S. C., Song, X., Rivieccio, M. & Brosnan, C. F. IL-1-regulated responses in astrocytes: relevance to injury and recovery. Glia 49, 161–176 (2005).

    Article  PubMed  Google Scholar 

  15. Bergsbaken, T., Fink, S. L. & Cookson, B. T. Pyroptosis: host cell death and inflammation. Nature Rev. Microbiol. 7, 99–109 (2009).

    Article  CAS  Google Scholar 

  16. Zhang, W. H. et al. Fundamental role of the Rip2/caspase-1 pathway in hypoxia and ischemia-induced neuronal cell death. Proc. Natl Acad. Sci. USA 100, 16012–16017 (2003). This study provides strong evidence for a caspase 1-dependent cell death pathway that is localized in neurons, using caspase 1-knockout mice.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. de Rivero Vaccari, J. P., Lotocki, G., Marcillo, A. E., Dietrich, W. D. & Keane, R. W. A molecular platform in neurons regulates inflammation after spinal cord injury. J. Neurosci. 28, 3404–3414 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. de Rivero Vaccari, J. P. et al. Therapeutic neutralization of the NLRP1 inflammasome reduces the innate immune response and improves histopathology after traumatic brain injury. J. Cereb. Blood Flow Metab. 29, 1251–1261 (2009). One of several related studies to propose a novel role for NLRP1 activation in the response to acute brain injury.

    Article  CAS  PubMed  Google Scholar 

  19. Silverman, W. R. et al. The pannexin 1 channel activates the inflammasome in neurons and astrocytes. J. Biol. Chem. 284, 18143–18151 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 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 

  21. Jamilloux, Y. et al. Inflammasome activation restricts Legionella pneumophila replication in primary microglial cells through flagellin detection. Glia 61, 539–549 (2013).

    Article  PubMed  Google Scholar 

  22. 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 

  23. 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  PubMed  PubMed Central  Google Scholar 

  24. Kofoed, E. M. & Vance, R. E. Innate immune recognition of bacterial ligands by NAIPs determines inflammasome specificity. Nature 477, 592–595 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zhao, Y. et al. The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus. Nature 477, 596–600 (2011).

    Article  CAS  PubMed  Google Scholar 

  26. Vinzing, M. et al. NAIP and Ipaf control Legionella pneumophila replication in human cells. J. Immunol. 180, 6808–6815 (2008).

    Article  CAS  PubMed  Google Scholar 

  27. Maier, J. K. et al. The neuronal apoptosis inhibitory protein is a direct inhibitor of caspases 3 and 7. J. Neurosci. 22, 2035–2043 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 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 

  29. Moayeri, M., Sastalla, I. & Leppla, S. H. Anthrax and the inflammasome. Microbes Infect. 14, 392–400 (2012).

    Article  CAS  PubMed  Google Scholar 

  30. Finger, J. N. et al. Autolytic proteolysis within the function to find domain (FIIND) is required for NLRP1 inflammasome activity. J. Biol. Chem. 287, 25030–25037 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ebrahimi, C. M., Sheen, T. R., Renken, C. W., Gottlieb, R. A. & Doran, K. S. Contribution of lethal toxin and edema toxin to the pathogenesis of anthrax meningitis. Infect. Immun. 79, 2510–2518 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Levinsohn, J. L. et al. Anthrax lethal factor cleavage of Nlrp1 is required for activation of the inflammasome. PLoS Pathog. 8, e1002638 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  34. D'Osualdo, A. et al. CARD8 and NLRP1 undergo autoproteolytic processing through a ZU5-like domain. PLoS ONE 6, e27396 (2011).

  35. Geldhoff, M. et al. Genetic variation in inflammasome genes is associated with outcome in bacterial meningitis. Immunogenetics 65, 9–16 (2013).

    Article  CAS  PubMed  Google Scholar 

  36. Bruey, J. M. et al. Bcl-2 and Bcl-XL regulate proinflammatory caspase-1 activation by interaction with NALP1. Cell 129, 45–56 (2007).

    Article  CAS  PubMed  Google Scholar 

  37. Deveraux, Q. L. et al. Cleavage of human inhibitor of apoptosis protein XIAP results in fragments with distinct specificities for caspases. EMBO J. 18, 5242–5251 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Labbe, K., McIntire, C. R., Doiron, K., Leblanc, P. M. & Saleh, M. Cellular inhibitors of apoptosis proteins cIAP1 and cIAP2 are required for efficient caspase-1 activation by the inflammasome. Immunity 35, 897–907 (2011).

    Article  CAS  PubMed  Google Scholar 

  39. Vince, J. E. et al. Inhibitor of apoptosis proteins limit RIP3 kinase-dependent interleukin-1 activation. Immunity 36, 215–227 (2012).

    Article  CAS  PubMed  Google Scholar 

  40. Pelegrin, P. & Surprenant, A. Pannexin-1 mediates large pore formation and interleukin-1β release by the ATP-gated P2X7 receptor. EMBO J. 25, 5071–5082 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Karatas, H. et al. Spreading depression triggers headache by activating neuronal Panx1 channels. Science 339, 1092–1095 (2013).

    Article  CAS  PubMed  Google Scholar 

  42. Qu, Y. et al. Pannexin-1 is required for ATP release during apoptosis but not for inflammasome activation. J. Immunol. 186, 6553–6561 (2011).

    Article  CAS  PubMed  Google Scholar 

  43. Bargiotas, P., Krenz, A., Monyer, H. & Schwaninger, M. Functional outcome of pannexin-deficient mice after cerebral ischemia. Channels (Austin) 6, 453–456 (2012).

    Article  CAS  Google Scholar 

  44. Hanstein, R. et al. Promises and pitfalls of a Pannexin1 transgenic mouse line. Front. Pharmacol. 4, 61 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  45. MacVicar, B. A. & Thompson, R. J. Non-junction functions of pannexin-1 channels. Trends Neurosci. 33, 93–102 (2010).

    Article  CAS  PubMed  Google Scholar 

  46. Pontillo, A., Catamo, E., Arosio, B., Mari, D. & Crovella, S. NALP1/NLRP1 genetic variants are associated with Alzheimer disease. Alzheimer Dis. Assoc. Disord. 26, 277–281 (2012).

    Article  CAS  PubMed  Google Scholar 

  47. Duncan, J. A. et al. Neisseria gonorrhoeae activates the proteinase cathepsin B to mediate the signaling activities of the NLRP3 and ASC-containing inflammasome. J. Immunol. 182, 6460–6469 (2009).

    Article  CAS  PubMed  Google Scholar 

  48. Ichinohe, T., Lee, H. K., Ogura, Y., Flavell, R. & Iwasaki, A. Inflammasome recognition of influenza virus is essential for adaptive immune responses. J. Exp. Med. 206, 79–87 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  50. Halle, A. et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-β. Nature Immunol. 9, 857–865 (2008). The first study to implicate inflammasome activation in response to a misfolded protein — in this case, amyloid-β.

    Article  CAS  Google Scholar 

  51. 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 

  52. Hornung, V. et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nature Immunol. 9, 847–856 (2008).

    Article  CAS  Google Scholar 

  53. Bauernfeind, F. G. et al. Cutting edge: NF-κB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J. Immunol. 183, 787–791 (2009).

    Article  CAS  PubMed  Google Scholar 

  54. Ferrari, D. et al. Extracellular ATP triggers IL-1 beta release by activating the purinergic P2Z receptor of human macrophages. J. Immunol. 159, 1451–1458 (1997).

    CAS  PubMed  Google Scholar 

  55. Piccini, A. et al. ATP is released by monocytes stimulated with pathogen-sensing receptor ligands and induces IL-1β and IL-18 secretion in an autocrine way. Proc. Natl Acad. Sci. USA 105, 8067–8072 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  57. Munoz-Planillo, R. et al. K+ efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter. Immunity 38, 1142–1153 (2013). This study reports that all activators of the NLRP3 inflammasome mediate their actions through the triggering of a K+ efflux.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Schorn, C. et al. Sodium overload and water influx activate the NALP3 inflammasome. J. Biol. Chem. 286, 35–41 (2011).

    Article  CAS  PubMed  Google Scholar 

  59. Compan, V. et al. Cell volume regulation modulates NLRP3 inflammasome activation. Immunity 37, 487–500 (2012). A recent study that proposes cell volume changes as a conserved mechanism for regulating NLRP3 inflammasome activation, including within neurons.

    Article  CAS  PubMed  Google Scholar 

  60. Chu, J. et al. Cholesterol-dependent cytolysins induce rapid release of mature IL-1β from murine macrophages in a NLRP3 inflammasome and cathepsin B-dependent manner. J. Leukoc. Biol. 86, 1227–1238 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Zaiss, A. K. et al. Antiviral antibodies target adenovirus to phagolysosomes and amplify the innate immune response. J. Immunol. 182, 7058–7068 (2009).

    Article  CAS  PubMed  Google Scholar 

  62. Hoegen, T. et al. The NLRP3 inflammasome contributes to brain injury in pneumococcal meningitis and is activated through ATP-dependent lysosomal cathepsin B release. J. Immunol. 187, 5440–5451 (2011). This study shows that NLPR3 activation promotes brain injury in pneumococcal meningitis. This contrasts with pneumococcal pneumonia, in which NLRP3 inflammasome activation is protective.

    Article  CAS  PubMed  Google Scholar 

  63. Codolo, G. et al. Triggering of inflammasome by aggregated α-synuclein, an inflammatory response in synucleinopathies. PLoS ONE 8, e55375 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Cruz, C. M. et al. ATP activates a reactive oxygen species-dependent oxidative stress response and secretion of proinflammatory cytokines in macrophages. J. Biol. Chem. 282, 2871–2879 (2007).

    Article  CAS  PubMed  Google Scholar 

  66. Zhou, R., Tardivel, A., Thorens, B., Choi, I. & Tschopp, J. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nature Immunol. 11, 136–140 (2010).

    Article  CAS  Google Scholar 

  67. Kaushik, D. K., Gupta, M., Kumawat, K. L. & Basu, A. NLRP3 inflammasome: key mediator of neuroinflammation in murine Japanese encephalitis. PLoS ONE 7, e32270 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Masters, S. L. et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes. Nature Immunol. 11, 897–904 (2010).

    Article  CAS  Google Scholar 

  69. Nakahira, K. et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nature Immunol. 12, 222–230 (2011).

    Article  CAS  Google Scholar 

  70. Zhou, R., Yazdi, A. S., Menu, P. & Tschopp, J. A role for mitochondria in NLRP3 inflammasome activation. Nature 469, 221–225 (2011).

    Article  CAS  PubMed  Google Scholar 

  71. Shimada, K. et al. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity 36, 401–414 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Subramanian, N., Natarajan, K., Clatworthy, M. R., Wang, Z. & Germain, R. N. The adaptor MAVS promotes NLRP3 mitochondrial localization and inflammasome activation. Cell 153, 348–361 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Ramos, H. J. et al. IL-1β signaling promotes CNS-intrinsic immune control of West Nile virus infection. PLoS Pathog. 8, e1003039 (2012). This study demonstrates a role for an inflammasome-dependent protective response during encephalitis caused by WNV.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Burguillos, M. A. et al. Caspase signalling controls microglia activation and neurotoxicity. Nature 472, 319–324 (2011).

    Article  CAS  PubMed  Google Scholar 

  75. Shi, F. et al. The NALP3 inflammasome is involved in neurotoxic prion peptide-induced microglial activation. J. Neuroinflammation 9, 73 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Hanamsagar, R., Torres, V. & Kielian, T. Inflammasome activation and IL-1β/IL-18 processing are influenced by distinct pathways in microglia. J. Neurochem. 119, 736–748 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Gulbransen, B. D. et al. Activation of neuronal P2X7 receptor–pannexin-1 mediates death of enteric neurons during colitis. Nature Med. 18, 600–604 (2012).

    Article  CAS  PubMed  Google Scholar 

  78. Kone-Paut, I. & Piram, M. Targeting interleukin-1β in CAPS (cryopyrin-associated periodic) syndromes: what did we learn? Autoimmun. Rev. 12, 77–80 (2012).

    Article  CAS  PubMed  Google Scholar 

  79. 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 

  80. Jin, T. et al. Structures of the HIN domain: DNA complexes reveal ligand binding and activation mechanisms of the AIM2 inflammasome and IFI16 receptor. Immunity 36, 561–571 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Kummer, J. A. et al. Inflammasome components NALP 1 and 3 show distinct but separate expression profiles in human tissues suggesting a site-specific role in the inflammatory response. J. Histochem. Cytochem. 55, 443–452 (2007).

    Article  CAS  PubMed  Google Scholar 

  82. Yin, Y. et al. Inflammasomes are differentially expressed in cardiovascular and other tissues. Int. J. Immunopathol. Pharmacol. 22, 311–322 (2009).

    Article  CAS  PubMed  Google Scholar 

  83. Guarda, G. et al. Differential expression of NLRP3 among hematopoietic cells. J. Immunol. 186, 2529–2534 (2011).

    Article  CAS  PubMed  Google Scholar 

  84. Tarallo, V. et al. DICER1 loss and Alu RNA induce age-related macular degeneration via the NLRP3 inflammasome and MyD88. Cell 149, 847–859 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Agard, N. J., Maltby, D. & Wells, J. A. Inflammatory stimuli regulate caspase substrate profiles. Mol. Cell. Proteomics 9, 880–893 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Griffin, W. S. et al. Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc. Natl Acad. Sci. USA 86, 7611–7615 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. McGuinness, M. C. et al. Human leukocyte antigens and cytokine expression in cerebral inflammatory demyelinative lesions of X-linked adrenoleukodystrophy and multiple sclerosis. J. Neuroimmunol. 75, 174–182 (1997).

    Article  CAS  PubMed  Google Scholar 

  89. Zaremba, J. & Losy, J. Interleukin-18 in acute ischaemic stroke patients. Neurol. Sci. 24, 117–124 (2003).

    Article  CAS  PubMed  Google Scholar 

  90. 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 

  91. 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).

    Article  CAS  Google Scholar 

  92. Lee, H. M. et al. Mycobacterium abscessus activates the NLRP3 inflammasome via Dectin-1-Syk and p62/SQSTM1. Immunol. Cell Biol. 90, 601–610 (2012).

    Article  CAS  PubMed  Google Scholar 

  93. Soong, G., Chun, J., Parker, D. & Prince, A. Staphylococcus aureus activation of caspase 1/calpain signaling mediates invasion through human keratinocytes. J. Infect. Dis. 205, 1571–1579 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Chien, H. & Dix, R. D. Evidence for multiple cell death pathways during development of experimental cytomegalovirus retinitis in mice with retrovirus-induced immunosuppression: apoptosis, necroptosis, and pyroptosis. J. Virol. 86, 10961–10978 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Troy, C. M., Stefanis, L., Prochiantz, A., Greene, L. A. & Shelanski, M. L. The contrasting roles of ICE family proteases and interleukin-1β in apoptosis induced by trophic factor withdrawal and by copper/zinc superoxide dismutase down-regulation. Proc. Natl Acad. Sci. USA 93, 5635–5640 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Guegan, C. et al. Instrumental activation of bid by caspase-1 in a transgenic mouse model of ALS. Mol. Cell. Neurosci. 20, 553–562 (2002).

    Article  CAS  PubMed  Google Scholar 

  97. Friedlander, R. M. et al. Expression of a dominant negative mutant of interleukin-1 beta converting enzyme in transgenic mice prevents neuronal cell death induced by trophic factor withdrawal and ischemic brain injury. J. Exp. Med. 185, 933–940 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Mehta, A., Prabhakar, M., Kumar, P., Deshmukh, R. & Sharma, P. L. Excitotoxicity: bridge to various triggers in neurodegenerative disorders. Eur. J. Pharmacol. 698, 6–18 (2013).

    Article  CAS  PubMed  Google Scholar 

  99. McNeela, E. A. et al. Pneumolysin activates the NLRP3 inflammasome and promotes proinflammatory cytokines independently of TLR4. PLoS Pathog. 6, e1001191 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Mitchell, A. J. et al. Inflammasome-dependent IFN-γ drives pathogenesis in Streptococcus pneumoniae meningitis. J. Immunol. 189, 4970–4980 (2012).

    Article  CAS  PubMed  Google Scholar 

  101. Zwijnenburg, P. J. et al. Interleukin-18 gene-deficient mice show enhanced defense and reduced inflammation during pneumococcal meningitis. J. Neuroimmunol. 138, 31–37 (2003).

    Article  CAS  PubMed  Google Scholar 

  102. Lee, H. M., Kang, J., Lee, S. J. & Jo, E. K. Microglial activation of the NLRP3 inflammasome by the priming signals derived from macrophages infected with mycobacteria. Glia 61, 441–452 (2013).

    Article  PubMed  Google Scholar 

  103. Kumar, M. et al. Inflammasome adaptor protein apoptosis-associated speck-like protein containing CARD (ASC) is critical for the immune response and survival in West Nile virus encephalitis. J. Virol. 87, 3655–3667 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Mori, I. et al. Impaired microglial activation in the brain of IL-18-gene-disrupted mice after neurovirulent influenza A virus infection. Virology 287, 163–170 (2001).

    Article  CAS  PubMed  Google Scholar 

  105. Sergerie, Y., Rivest, S. & Boivin, G. Tumor necrosis factor-α and interleukin-1β play a critical role in the resistance against lethal herpes simplex virus encephalitis. J. Infect. Dis. 196, 853–860 (2007).

    Article  CAS  PubMed  Google Scholar 

  106. 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).

    Article  CAS  PubMed  Google Scholar 

  107. Wheeler, R. D. et al. No role for interleukin-18 in acute murine stroke-induced brain injury. J. Cereb. Blood Flow Metab. 23, 531–535 (2003).

    Article  CAS  PubMed  Google Scholar 

  108. Pradillo, J. M. et al. Delayed administration of interleukin-1 receptor antagonist reduces ischemic brain damage and inflammation in comorbid rats. J. Cereb. Blood Flow Metab. 32, 1810–1819 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Boutin, H. et al. Role of IL-1α and IL-1β in ischemic brain damage. J. Neurosci. 21, 5528–5534 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Afonina, I. S. et al. Granzyme B-dependent proteolysis acts as a switch to enhance the proinflammatory activity of IL-1α. Mol. Cell 44, 265–278 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Zheng, Y., Humphry, M., Maguire, J. J., Bennett, M. R. & Clarke, M. C. Intracellular interleukin-1 receptor 2 binding prevents cleavage and activity of interleukin-1α, controlling necrosis-induced sterile inflammation. Immunity 38, 285–295 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  113. Abulafia, D. P. et al. Inhibition of the inflammasome complex reduces the inflammatory response after thromboembolic stroke in mice. J. Cereb. Blood Flow Metab. 29, 534–544 (2009).

    Article  CAS  PubMed  Google Scholar 

  114. Frederick Lo, C., Ning, X., Gonzales, C. & Ozenberger, B. A. Induced expression of death domain genes NALP1 and NALP5 following neuronal injury. Biochem. Biophys. Res. Commun. 366, 664–669 (2008).

    Article  CAS  PubMed  Google Scholar 

  115. Adamczak, S. et al. Inflammasome proteins in cerebrospinal fluid of brain-injured patients as biomarkers of functional outcome: clinical article. J. Neurosurg. 117, 1119–1125 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Gris, D. et al. NLRP3 plays a critical role in the development of experimental autoimmune encephalomyelitis by mediating Th1 and Th17 responses. J. Immunol. 185, 974–981 (2010).

    Article  CAS  PubMed  Google Scholar 

  117. Inoue, M., Williams, K. L., Gunn, M. D. & Shinohara, M. L. NLRP3 inflammasome induces chemotactic immune cell migration to the CNS in experimental autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 109, 10480–10485 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Lalor, S. J. et al. Caspase-1-processed cytokines IL-1β and IL-18 promote IL-17 production by γδ and CD4 T cells that mediate autoimmunity. J. Immunol. 186, 5738–5748 (2011).

    Article  CAS  PubMed  Google Scholar 

  119. Jha, S. et al. The inflammasome sensor, NLRP3, regulates CNS inflammation and demyelination via caspase-1 and interleukin-18. J. Neurosci. 30, 15811–15820 (2010). This study shows that mice deficient in a particular inflammasome or caspase 1 activation pathway exhibit less neurological disease owing to an ameliorated inflammatory response.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Mason, J. L., Suzuki, K., Chaplin, D. D. & Matsushima, G. K. Interleukin-1β promotes repair of the CNS. J. Neurosci. 21, 7046–7052 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Meissner, F., Molawi, K. & Zychlinsky, A. Mutant superoxide dismutase 1-induced IL-1β accelerates ALS pathogenesis. Proc. Natl Acad. Sci. USA 107, 13046–13050 (2010). This study demonstrates that inflammasome activation in response to SOD1 enhances pathogenesis in an ALS model.

    Article  PubMed  PubMed Central  Google Scholar 

  122. Craft, J. M., Watterson, D. M., Hirsch, E. & Van Eldik, L. J. Interleukin 1 receptor antagonist knockout mice show enhanced microglial activation and neuronal damage induced by intracerebroventricular infusion of human β-amyloid. J. Neuroinflammation 2, 15 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Shaftel, S. S. et al. Sustained hippocampal IL-1β overexpression mediates chronic neuroinflammation and ameliorates Alzheimer plaque pathology. J. Clin. Invest. 117, 1595–1604 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Heneka, M. T. et al. NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature 493, 674–678 (2013). This study shows that NLRP3 inflammasome activation adversely affects disease outcome in a mouse model of Alzheimer's disease.

    Article  CAS  PubMed  Google Scholar 

  125. Elinav, E. et al. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145, 745–757 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Vladimer, G. I. et al. The NLRP12 inflammasome recognizes Yersinia pestis. Immunity 37, 96–107 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Akhter, A. et al. Caspase-11 promotes the fusion of phagosomes harboring pathogenic bacteria with lysosomes by modulating actin polymerization. Immunity 37, 35–47 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Broz, P. et al. Caspase-11 increases susceptibility to Salmonella infection in the absence of caspase-1. Nature 490, 288–291 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Rathinam, V. A. et al. TRIF licenses caspase-11-dependent NLRP3 inflammasome activation by Gram-negative bacteria. Cell 150, 606–619 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. von Moltke, J. et al. Rapid induction of inflammatory lipid mediators by the inflammasome in vivo. Nature 490, 107–111 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Lu, J. X. et al. Molecular structure of β-amyloid fibrils in Alzheimer's disease brain tissue. Cell 154, 1257–1268 (2013).

    Article  CAS  PubMed  Google Scholar 

  132. Yang, E. J., Kim, S., Kim, J. S. & Choi, I. H. Inflammasome formation and IL-1β release by human blood monocytes in response to silver nanoparticles. Biomaterials 33, 6858–6867 (2012).

    Article  CAS  PubMed  Google Scholar 

  133. Liao, Y. H. et al. HMG-CoA reductase inhibitors activate caspase-1 in human monocytes depending on ATP release and P2X7 activation. J. Leukoc. Biol. 93, 289–299 (2013).

    Article  CAS  PubMed  Google Scholar 

  134. Ruperto, N. et al. Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis. N. Engl. J. Med. 367, 2396–2406 (2012).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Coll, R. C. & O'Neill, L. A. The cytokine release inhibitory drug CRID3 targets ASC oligomerisation in the NLRP3 and AIM2 inflammasomes. PLoS ONE 6, e29539 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Deroide, N. et al. MFGE8 inhibits inflammasome-induced IL-1β production and limits postischemic cerebral injury. J. Clin. Invest. 123, 1176–1181 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Yan, Y. et al. Omega-3 fatty acids prevent inflammation and metabolic disorder through inhibition of NLRP3 inflammasome activation. Immunity 38, 1154–1163 (2013).

    Article  CAS  PubMed  Google Scholar 

  139. Prinz, M., Priller, J., Sisodia, S. S. & Ransohoff, R. M. Heterogeneity of CNS myeloid cells and their roles in neurodegeneration. Nature Neurosci. 14, 1227–1235 (2011).

    Article  CAS  PubMed  Google Scholar 

  140. Czirr, E. & Wyss-Coray, T. The immunology of neurodegeneration. J. Clin. Invest. 122, 1156–1163 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Hyman, B. T. & Yuan, J. Apoptotic and non-apoptotic roles of caspases in neuronal physiology and pathophysiology. Nature Rev. Neurosci. 13, 395–406 (2012).

    Article  CAS  Google Scholar 

  142. Kaczmarek, A., Vandenabeele, P. & Krysko, D. V. Necroptosis: the release of damage-associated molecular patterns and its physiological relevance. Immunity 38, 209–223 (2013).

    Article  CAS  PubMed  Google Scholar 

  143. Chavez-Valdez, R., Martin, L. J., Flock, D. L. & Northington, F. J. Necrostatin-1 attenuates mitochondrial dysfunction in neurons and astrocytes following neonatal hypoxia-ischemia. Neuroscience 219, 192–203 (2012).

    Article  CAS  PubMed  Google Scholar 

  144. Li, Z. et al. Caspase-3 activation via mitochondria is required for long-term depression and AMPA receptor internalization. Cell 141, 859–871 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Graham, R. K., Ehrnhoefer, D. E. & Hayden, M. R. Caspase-6 and neurodegeneration. Trends Neurosci. 34, 646–656 (2011).

    Article  CAS  PubMed  Google Scholar 

  146. Dostert, C. et al. Malarial hemozoin is a Nalp3 inflammasome activating danger signal. PLoS ONE 4, e6510 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Reimer, T. et al. Experimental cerebral malaria progresses independently of the Nlrp3 inflammasome. Eur. J. Immunol. 40, 764–769 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Hafner-Bratkovic, I., Bencina, M., Fitzgerald, K. A., Golenbock, D. & Jerala, R. NLRP3 inflammasome activation in macrophage cell lines by prion protein fibrils as the source of IL-1β and neuronal toxicity. Cell. Mol. Life Sci. 69, 4215–4228 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

J.G.W. is supported by an Alberta Innovates-Health Solutions (AIHS) Fellowship. D.A.M. is supported by an AIHS Clinical Senior Scholar Award and holds a Canada Research Chair in Inflammation and Kidney Disease. C.P. is supported by a Canada Research Chair in Neurological Infection and Immunity. The authors thank P. Smith and B. Kerr for advice and helpful comments on this manuscript.

Author information

Authors and Affiliations

  1. Department of Medicine (Neurology), University of Alberta, Edmonton, T6G 2S2, Alberta, Canada

    John G. Walsh & Christopher Power

  2. Department of Medicine (Nephrology), University of Calgary, Calgary, T2N 4N1, Alberta, Canada

    Daniel A. Muruve

Authors
  1. John G. Walsh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel A. Muruve
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christopher Power
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Christopher Power.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

Mononuclear phagocytic cells

A family of non-lymphocyte immune cells, including monocytes, macrophages, microglia and dendritic cells.

Pathogen-associated molecular patterns

Specific elements that are produced by microorganisms and that can induce innate immune responses. These elements are recognized by specific receptors that are expressed at the surface of macrophages, dendritic cells and microglia.

Danger-associated molecular patterns

(Also known as damage-associated molecular patterns.) Cellular molecules that are exposed after damage-induced necrosis. They are recognized by specialized receptors that are expressed at the surface of macrophages, dendritic cells and microglia.

Innate immunity

Immune responses based on the sensing of conserved pathogen or danger-associated molecular patterns (PAMPs or DAMPs, respectively) by germline-encoded pattern-recognition receptors without previous recognition or memory, unlike adaptive immunity.

Pyroptosis

A caspase 1-dependent form of programmed cell death that is characterized by necrosis-like swelling and rupture of the cell membrane.

Flagellin

The primary component protein of bacterial flagella.

PrgJ

A protein component of the Gram-negative type III secretion system (T3SS). The T3SS is a needle-like structure found on the bacterial surface, which enables the injection of bacterial proteins into host cells in order to facilitate infection.

Crohn's disease

A chronic inflammatory disease of the intestines (especially the colon and ileum) that is associated with ulcers and fistulae.

Two-signal system

In reference to the two-step model of inflammasome activation: following an initial priming signal (signal 1) to induce expression of pro-interleukin-1β, a second signal (signal 2) is required to trigger formation of the inflammasome complex and activate caspase 1, which can then cleave interleukin-1β into its mature form before its eventual secretion.

Non-myeloid cell types

Cells of the CNS other than microglia and macrophages, including astrocytes, oligodendrocytes and neurons.

T cell priming

The process by which naive T cells are presented with an antigen in an immunogenic form, leading to their maturation into effector cells.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Walsh, J., Muruve, D. & Power, C. Inflammasomes in the CNS. Nat Rev Neurosci 15, 84–97 (2014). https://doi.org/10.1038/nrn3638

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn3638

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