Skip to main content
See More

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:

Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3

Nature volume 440, pages 233–236 (2006)Cite this article

Abstract

Missense mutations in the CIAS1 gene cause three autoinflammatory disorders: familial cold autoinflammatory syndrome, Muckle–Wells syndrome and neonatal-onset multiple-system inflammatory disease1. Cryopyrin (also called Nalp3), the product of CIAS1, is a member of the NOD-LRR protein family that has been linked to the activation of intracellular host defence signalling pathways2,3. Cryopyrin forms a multi-protein complex termed ‘the inflammasome’, which contains the apoptosis-associated speck-like protein (ASC) and caspase-1, and promotes caspase-1 activation and processing of pro-interleukin (IL)-1β (ref. 4). Here we show the effect of cryopyrin deficiency on inflammasome function and immune responses. Cryopyrin and ASC are essential for caspase-1 activation and IL-1β and IL-18 production in response to bacterial RNA and the imidazoquinoline compounds R837 and R848. In contrast, secretion of tumour-necrosis factor-α and IL-6, as well as activation of NF-κB and mitogen-activated protein kinases (MAPKs) were unaffected by cryopyrin deficiency. Furthermore, we show that Toll-like receptors and cryopyrin control the secretion of IL-1β and IL-18 through different intracellular pathways. These results reveal a critical role for cryopyrin in host defence through bacterial RNA-mediated activation of caspase-1, and provide insights regarding the pathogenesis of autoinflammatory syndromes.

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 required for IL-1β and IL-18 secretion in response to imidazoquinoline compounds R837 and R848.
Figure 2: Caspase-1 processing and NF-κB activation in mutant macrophages stimulated with R837 or R848.
Figure 3: Cryopyrin is essential for activation of caspase-1 in response to bacterial RNA.
Figure 4: R837 and LPS cooperate in the production of pro-inflammatory cytokines in a cryopyrin-dependent manner.

Similar content being viewed by others

References

  1. Stojanov, S. & Kastner, D. L. Familial autoinflammatory diseases: genetics, pathogenesis and treatment. Curr. Opin. Rheumatol. 17, 586–599 (2005)

    Article  CAS  Google Scholar 

  2. Inohara, N., Chamaillard, M., McDonald, C. & Nunez, G. NOD-LRR proteins: role in host-microbial interactions and inflammatory disease. Annu. Rev. Biochem. 74, 355–383 (2005)

    Article  CAS  Google Scholar 

  3. Athman, R. & Philpott, D. Innate immunity via Toll-like receptors and Nod proteins. Curr. Opin. Microbiol. 7, 25–32 (2004)

    Article  CAS  Google Scholar 

  4. 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 

  5. Perregaux, D. G., McNiff, P., Laliberte, R., Conklyn, M. & Gabel, C. A. ATP acts as an agonist to promote stimulus-induced secretion of IL-1β and IL-18 in human blood. J. Immunol. 165, 4615–4623 (2000)

    Article  CAS  Google Scholar 

  6. Hemmi, H. et al. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nature Immunol. 3, 196–200 (2002)

    Article  CAS  Google Scholar 

  7. Jurk, M. et al. Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848. Nature Immunol. 3, 499 (2002)

    Article  CAS  Google Scholar 

  8. Dinarello, C. A. Interleukin-1β, interleukin-18, and the interleukin-1β converting enzyme. Ann. NY Acad. Sci. 856, 1–11 (1998)

    Article  ADS  CAS  Google Scholar 

  9. 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 

  10. Dockrell, D. H. & Kinghorn, G. R. Imiquimod and resiquimod as novel immunomodulators. J. Antimicrob. Chemother. 48, 751–755 (2001)

    Article  CAS  Google Scholar 

  11. Janssen, R., Verhard, E., Lankester, A., Ten Cate, R. & van Dissel, J. T. Enhanced interleukin-1β and interleukin-18 release in a patient with chronic infantile neurologic, cutaneous, articular syndrome. Arthritis Rheum. 50, 3329–3333 (2004)

    Article  Google Scholar 

  12. O'Connor, W. Jr, Harton, J. A., Zhu, X., Linhoff, M. W. & Ting, J. P. Cutting edge: CIAS1/cryopyrin/PYPAF1/NALP3/CATERPILLER 1.1 is an inducible inflammatory mediator with NF-κB suppressive properties. J. Immunol. 171, 6329–6333 (2003)

    Article  CAS  Google Scholar 

  13. Netea, M. G., Kullberg, B. J., Verschueren, I. & Van Der Meer, J. W. Interleukin-18 induces production of proinflammatory cytokines in mice: no intermediate role for the cytokines of the tumour necrosis factor family and interleukin-1β. Eur. J. Immunol. 30, 3057–3060 (2000)

    Article  CAS  Google Scholar 

  14. 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 

  15. 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 

  16. Heil, F. et al. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 303, 1526–1529 (2004)

    Article  ADS  CAS  Google Scholar 

  17. Lund, J. M. et al. Recognition of single-stranded RNA viruses by Toll-like receptor 7. Proc. Natl Acad. Sci. USA 101, 5598–5603 (2004)

    Article  ADS  CAS  Google Scholar 

  18. Diebold, S. S., Kaisho, T., Hemmi, H., Akira, S. & Reis e Sousa, C. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303, 1529–1531 (2004)

    Article  ADS  CAS  Google Scholar 

  19. Kariko, K., Buckstein, M., Ni, H. & Weissman, D. Suppression of RNA recognition by toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. Immunity 23, 165–175 (2005)

    Article  CAS  Google Scholar 

  20. Koski, G. K. et al. Cutting edge: innate immune system discriminates between RNA containing bacterial versus eukaryotic structural features that prime for high-level IL-12 secretion by dendritic cells. J. Immunol. 172, 3989–3993 (2004)

    Article  CAS  Google Scholar 

  21. Craft, N. et al. The TLR7 agonist imiquimod enhances the anti-melanoma effects of a recombinant Listeria monocytogenes vaccine. J. Immunol. 175, 1983–1990 (2005)

    Article  CAS  Google Scholar 

  22. Harrison, C. J., Jenski, L., Voychehovski, T. & Bernstein, D. I. Modification of immunological responses and clinical disease during topical R-837 treatment of genital HSV-2 infection. Antiviral Res. 10, 209–223 (1988)

    Article  CAS  Google Scholar 

  23. Tomai, M. A. et al. Immunomodulating and antiviral activities of the imidazoquinoline S-28463. Antiviral Res. 28, 253–264 (1995)

    Article  CAS  Google Scholar 

  24. Marks, R. et al. Imiquimod 5% cream in the treatment of superficial basal cell carcinoma: results of a multicenter 6-week dose-response trial. J. Am. Acad. Dermatol. 44, 807–813 (2001)

    Article  CAS  Google Scholar 

  25. Özören, N. et al. Distinct roles of TLR2 and the adaptor ASC in IL-1β/IL-18 secretion and host defense against Listeria monocytogenes. J. Immunol. (submitted)

  26. Lamkanfi, M., Kalai, M., Saelens, X., Declercq, W. & Vandenabeele, P. Caspase-1 activates nuclear factor of the κ-enhancer in B cells independently of its enzymatic activity. J. Biol. Chem. 279, 24785–24793 (2004)

    Article  CAS  Google Scholar 

  27. 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 

Download references

Acknowledgements

We thank D. Golenbock and P. Lin for providing mouse bone marrow, S. Bauer for the gift of R848, and J. Ting for anti-cryopyrin antibody. We thank C. McDonald and N. Inohara for discussions and advice, and the Cellular Immunology Core Facility of the University of Michigan Cancer Center for technical support. This work was supported by grants from the National Institutes of Health to G.N. T.-D.K. is supported by an NIH training grant. L.F. is the recipient of a postdoctoral fellowship from the Fondazione Italiana Ricerca sul Cancro. M.B.-M. is supported by a postdoctoral fellowship from the Fondation pour la Recherche Medicale.

Author information

Author notes

  1. John Bertin & Ethan P. Grant

    Present address: Synta Pharmaceuticals, 45 Hartwell Avenue, Lexington, Massachusetts, 02421, USA

  2. Anthony Coyle

    Present address: MedImmune Inc., 1 MedImmune Way, Gaithersburg, Maryland, 20878, USA

Authors and Affiliations

  1. Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan, 48109, USA

    Thirumala-Devi Kanneganti, Nesrin Özören, Mathilde Body-Malapel, Amal Amer, Jong-Hwan Park, Luigi Franchi, Joel Whitfield & Gabriel Núñez

  2. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, 63110, USA

    Winfried Barchet & Marco Colonna

  3. Department of Molecular Biomedical Research, Ghent University, B-9052, Zwijnaarde-Gent, Belgium

    Peter Vandenabeele

  4. Millennium Pharmaceuticals Inc., Cambridge, Massachusetts, 02139, USA

    John Bertin, Anthony Coyle & Ethan P. Grant

  5. Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, 565-0871, Osaka, Japan

    Shizuo Akira

Authors
  1. Thirumala-Devi Kanneganti
    View author publications

    Search author on:PubMed Google Scholar

  2. Nesrin Özören
    View author publications

    Search author on:PubMed Google Scholar

  3. Mathilde Body-Malapel
    View author publications

    Search author on:PubMed Google Scholar

  4. Amal Amer
    View author publications

    Search author on:PubMed Google Scholar

  5. Jong-Hwan Park
    View author publications

    Search author on:PubMed Google Scholar

  6. Luigi Franchi
    View author publications

    Search author on:PubMed Google Scholar

  7. Joel Whitfield
    View author publications

    Search author on:PubMed Google Scholar

  8. Winfried Barchet
    View author publications

    Search author on:PubMed Google Scholar

  9. Marco Colonna
    View author publications

    Search author on:PubMed Google Scholar

  10. Peter Vandenabeele
    View author publications

    Search author on:PubMed Google Scholar

  11. John Bertin
    View author publications

    Search author on:PubMed Google Scholar

  12. Anthony Coyle
    View author publications

    Search author on:PubMed Google Scholar

  13. Ethan P. Grant
    View author publications

    Search author on:PubMed Google Scholar

  14. Shizuo Akira
    View author publications

    Search author on:PubMed Google Scholar

  15. Gabriel Núñez
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to Gabriel Núñez.

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 Figures

This file contains Supplementary Figures 1–9. (PDF 307 kb)

Supplementary Figure Legends

This file contains legends for the above Supplementary Figures. (DOC 49 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kanneganti, TD., Özören, N., Body-Malapel, M. et al. Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3. Nature 440, 233–236 (2006). https://doi.org/10.1038/nature04517

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/nature04517

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