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.

  • Letter
  • Published:

Cryopyrin activates the inflammasome in response to toxins and ATP

Nature volume 440, pages 228–232 (2006)Cite this article

Abstract

A crucial part of the innate immune response is the assembly of the inflammasome, a cytosolic complex of proteins that activates caspase-1 to process the proinflammatory cytokines interleukin (IL)-1β and IL-18. The adaptor protein ASC is essential for inflammasome function1,2, binding directly to caspase-1 (refs 3, 4), but the triggers of this interaction are less clear. ASC also interacts with the adaptor cryopyrin (also known as NALP3 or CIAS1)5,6. Activating mutations in cryopyrin are associated with familial cold autoinflammatory syndrome, Muckle–Wells syndrome and neonatal onset multisystem inflammatory disease, diseases that are characterized by excessive production of IL-1β5,7. Here we show that cryopyrin-deficient macrophages cannot activate caspase-1 in response to Toll-like receptor agonists plus ATP, the latter activating the P2X7 receptor to decrease intracellular K+ levels8,9. The release of IL-1β in response to nigericin, a potassium ionophore, and maitotoxin, a potent marine toxin, was also found to be dependent on cryopyrin. In contrast to Asc-/- macrophages, cells deficient in the gene encoding cryopyrin (Cias1-/-) activated caspase-1 and secreted normal levels of IL-1β and IL-18 when infected with Gram-negative Salmonella typhimurium or Francisella tularensis. Macrophages exposed to Gram-positive Staphylococcus aureus or Listeria monocytogenes, however, required both ASC and cryopyrin to activate caspase-1 and secrete IL-1β. Therefore, cryopyrin is essential for inflammasome activation in response to signalling pathways triggered specifically by ATP, nigericin, maitotoxin, S. aureus or L. monocytogenes.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: Cryopyrin is essential for caspase-1 activation and IL-1β secretion in response to TLR agonists and ATP.
Figure 2: Cryopyrin is essential for caspase-1 activation and IL-1β secretion in response to TLR agonists plus nigericin or maitotoxin.
Figure 3: MDP triggers NOD2-dependent, cryopyrin-independent NF-κB and ERK signalling.
Figure 4: L. monocytogenes and S. aureus induce cryopyrin-dependent caspase-1 activation and IL-1β secretion.

Similar content being viewed by others

References

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

    Article  ADS  CAS  Google Scholar 

  2. 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)

    Article  CAS  Google Scholar 

  3. Srinivasula, S. M. et al. The PYRIN-CARD protein ASC is an activating adaptor for caspase-1. J. Biol. Chem. 277, 21119–21122 (2002)

    Article  CAS  Google Scholar 

  4. Wang, L. et al. PYPAF7, a novel PYRIN-containing Apaf1-like protein that regulates activation of NF-κB and caspase-1-dependent cytokine processing. J. Biol. Chem. 277, 29874–29880 (2002)

    Article  CAS  Google Scholar 

  5. 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  Google Scholar 

  6. Dowds, T. A., Masumoto, J., Zhu, L., Inohara, N. & Nunez, G. Cryopyrin-induced interleukin 1β secretion in monocytic cells: enhanced activity of disease-associated mutants and requirement for ASC. J. Biol. Chem. 279, 21924–21928 (2004)

    Article  CAS  Google Scholar 

  7. Ting, J. P. & Davis, B. K. CATERPILLER: a novel gene family important in immunity, cell death, and diseases. Annu. Rev. Immunol. 23, 387–414 (2005)

    CAS  Google Scholar 

  8. Perregaux, D. & Gabel, C. A. Interleukin-1β maturation and release in response to ATP and nigericin. Evidence that potassium depletion mediated by these agents is a necessary and common feature of their activity. J. Biol. Chem. 269, 15195–15203 (1994)

    CAS  PubMed  Google Scholar 

  9. Solle, M. et al. Altered cytokine production in mice lacking P2X7 receptors. J. Biol. Chem. 276, 125–132 (2001)

    Article  CAS  Google Scholar 

  10. Hogquist, K. A., Nett, M. A., Unanue, E. R. & Chaplin, D. D. Interleukin 1 is processed and released during apoptosis. Proc. Natl Acad. Sci. USA 88, 8485–8489 (1991)

    Article  ADS  CAS  Google Scholar 

  11. Yamamoto, M. et al. ASC is essential for LPS-induced activation of procaspase-1 independently of TLR-associated signal adaptor molecules. Genes Cells 9, 1055–1067 (2004)

    Article  CAS  Google Scholar 

  12. Poltorak, A. et al. Defective LPS signalling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282, 2085–2088 (1998)

    Article  ADS  CAS  Google Scholar 

  13. Wang, S. et al. Murine caspase-11, an ICE-interacting protease, is essential for the activation of ICE. Cell 92, 501–509 (1998)

    Article  CAS  Google Scholar 

  14. Schilling, W. P., Wasylyna, T., Dubyak, G. R., Humphreys, B. D. & Sinkins, W. G. Maitotoxin and P2Z/P2X7 purinergic receptor stimulation activate a common cytolytic pore. Am. J. Physiol. 277, C766–C776 (1999)

    Article  CAS  Google Scholar 

  15. Verhoef, P. A., Kertesy, S. B., Estacion, M., Schilling, W. P. & Dubyak, G. R. Maitotoxin induces biphasic interleukin-1β secretion and membrane blebbing in murine macrophages. Mol. Pharmacol. 66, 909–920 (2004)

    CAS  PubMed  Google Scholar 

  16. 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  Google Scholar 

  17. Martinon, F., Agostini, L., Meylan, E. & Tschopp, J. Identification of bacterial muramyl dipeptide as activator of the NALP3/cryopyrin inflammasome. Curr. Biol. 14, 1929–1934 (2004)

    Article  CAS  Google Scholar 

  18. Girardin, S. E. et al. Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J. Biol. Chem. 278, 8869–8872 (2003)

    Article  CAS  Google Scholar 

  19. Kobayashi, K. S. et al. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 307, 731–734 (2005)

    Article  ADS  CAS  Google Scholar 

  20. Maeda, S. et al. Nod2 mutation in Crohn's disease potentiates NF-κB activity and IL-1beta processing. Science 307, 734–738 (2005)

    Article  ADS  CAS  Google Scholar 

  21. Damiano, J. S., Newman, R. M. & Reed, J. C. Multiple roles of CLAN (caspase-associated recruitment domain, leucine-rich repeat, and NAIP CIIA HET-E, and TP1-containing protein) in the mammalian innate immune response. J. Immunol. 173, 6338–6345 (2004)

    Article  CAS  Google Scholar 

  22. 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  Google Scholar 

  23. McDermott, M. F. Genetic clues to understanding periodic fevers, and possible therapies. Trends Mol. Med. 8, 550–554 (2002)

    Article  CAS  Google Scholar 

  24. Feldmann, J. et al. Chronic infantile neurological cutaneous and articular syndrome is caused by mutations in CIAS1, a gene highly expressed in polymorphonuclear cells and chondrocytes. Am. J. Hum. Genet. 71, 198–203 (2002)

    Article  CAS  Google Scholar 

  25. Aganna, E. et al. Association of mutations in the NALP3/CIAS1/PYPAF1 gene with a broad phenotype including recurrent fever, cold sensitivity, sensorineural deafness, and AA amyloidosis. Arthritis Rheum. 46, 2445–2452 (2002)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank members of the Dixit laboratory for discussions, and M. Bauer, J. Starks, C. Olsson, M. Osborn, J. Hongo, M. Bever, J. Cupp and H. Maecker for technical assistance. S. aureus strains were provided by T. Foster. L. monocytogenes LLO mutant was provided by D. Portnoy. This work was supported by NIH grants awarded to D.M.M. and a fellowship from the Giannini Family Foundation awarded to D.S.W.

Author information

Authors and Affiliations

  1. Molecular Oncology Department,

    Sanjeev Mariathasan, Kim Newton, Karen O'Rourke & Vishva M. Dixit

  2. Physiology Department,

    Meron Roose-Girma

  3. Immunology Department, Genentech Inc, 1 DNA Way, South San, California, 94080, Francisco, USA

    Jacqueline McBride & Wyne P. Lee

  4. Departments of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, 94305, USA

    David S. Weiss & Denise M. Monack

  5. Department of Microbiology, New York University School of Medicine, New York, New York, 10016, USA

    Yvette Weinrauch

Authors
  1. Sanjeev Mariathasan
    View author publications

    Search author on:PubMed Google Scholar

  2. David S. Weiss
    View author publications

    Search author on:PubMed Google Scholar

  3. Kim Newton
    View author publications

    Search author on:PubMed Google Scholar

  4. Jacqueline McBride
    View author publications

    Search author on:PubMed Google Scholar

  5. Karen O'Rourke
    View author publications

    Search author on:PubMed Google Scholar

  6. Meron Roose-Girma
    View author publications

    Search author on:PubMed Google Scholar

  7. Wyne P. Lee
    View author publications

    Search author on:PubMed Google Scholar

  8. Yvette Weinrauch
    View author publications

    Search author on:PubMed Google Scholar

  9. Denise M. Monack
    View author publications

    Search author on:PubMed Google Scholar

  10. Vishva M. Dixit
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to Vishva M. Dixit.

Ethics declarations

Competing interests

Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Notes

This file contains Supplementary Methods and Supplementary Figures 1–6. (PDF 1354 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mariathasan, S., Weiss, D., Newton, K. et al. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440, 228–232 (2006). https://doi.org/10.1038/nature04515

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature04515

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