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.

  • Article
  • Published:

Dectin-1 is an extracellular pathogen sensor for the induction and processing of IL-1β via a noncanonical caspase-8 inflammasome

Nature Immunology volume 13, pages 246–254 (2012)Cite this article

Subjects

This article has been updated

Abstract

Production of the proinflammatory cytokine interleukin 1β (IL-1β) by dendritic cells is crucial in host defense. Here we identify a previously unknown role for dectin-1 in the activation of a noncanonical caspase-8 inflammasome in response to fungi and mycobacteria. Dectin-1 induced both the production and maturation of IL-1β through signaling routes mediated by the kinase Syk. Whereas the CARD9–Bcl-10–MALT1 scaffold directed IL1B transcription, the recruitment of MALT1–caspase-8 and ASC into this scaffold was crucial for processing of pro-IL-1β by caspase-8. In contrast to activation of the canonical caspase-1 inflammasome, which requires additional activation of cytosolic receptors, activation of the noncanonical caspase-8 inflammasome was independent of pathogen internalization. Thus, dectin-1 acted as an extracellular sensor for pathogens that induced both IL-1β production and maturation through a noncanonical caspase-8-dependent inflammasome for protective immunity.

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: Dectin-1 induces both inflammasome-independent and inflammasome-dependent processing of pro-IL-1β.
Figure 2: Dectin-1-induced caspase-8 activity is required for the processing of pro-IL-1β.
Figure 3: Dectin-1 signaling induces the formation of a CARD9–Bcl-10–MALT1–caspase-8–ASC complex.
Figure 4: Fungal recognition by dectin-1 induces caspase-8-mediated pro-IL-1β.
Figure 5: Extracellular recognition of fungi by dectin-1 is sufficient for caspase-8-mediated processing of pro-IL-1β, whereas inflammasome activation requires internalization of fungi by dectin-1.
Figure 6: Candida and Aspergillus strains induce caspase-8-mediated processing of pro-IL-1β via dectin-1.
Figure 7: Dectin-1-induced activation of caspase-8 contributes to pro-IL-1β processing in response to mycobacteria.

Similar content being viewed by others

Change history

  • 03 February 2012

    In the version of this article initially published online, the first sentence of the third paragraph in the Discussion section was incorrect. It should begin "In contrast to the processing of pro-IL-1β via caspase-8...". The error has been corrected for the print, PDF and HTML versions of this article.

References

  1. Romani, L. Cell mediated immunity to fungi: a reassessment. Med. Mycol. 46, 515–529 (2008).

    Article  CAS  Google Scholar 

  2. Segal, B.H. Aspergillosis. N. Engl. J. Med. 360, 1870–1884 (2009).

    Article  CAS  Google Scholar 

  3. van Beelen, A.J. et al. Stimulation of the intracellular bacterial sensor NOD2 programs dendritic cells to promote interleukin-17 production in human memory T cells. Immunity 27, 660–669 (2007).

    Article  CAS  Google Scholar 

  4. Weaver, C.T. & Hatton, R.D. Interplay between the TH17 and TReg cell lineages: a (co-)evolutionary perspective. Nat. Rev. Immunol. 9, 883–889 (2009).

    Article  CAS  Google Scholar 

  5. Louten, J., Boniface, K. & de Waal Malefyt, R. Development and function of TH17 cells in health and disease. J. Allergy Clin. Immunol. 123, 1004–1011 (2009).

    Article  CAS  Google Scholar 

  6. Ouyang, W., Kolls, J.K. & Zheng, Y. The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity 28, 454–467 (2008).

    Article  CAS  Google Scholar 

  7. Geijtenbeek, T.B.H. & Gringhuis, S.I. Signalling through C-type lectin receptors: shaping immune responses. Nat. Rev. Immunol. 9, 465–479 (2009).

    Article  CAS  Google Scholar 

  8. Medzhitov, R. Recognition of microorganisms and activation of the immune response. Nature 449, 819–826 (2007).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  10. Romani, L. Immunity to fungal infections. Nat. Rev. Immunol. 11, 275–288 (2011).

    Article  CAS  Google Scholar 

  11. Gross, O. et al. Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity. Nature 442, 651–656 (2006).

    Article  CAS  Google Scholar 

  12. LeibundGut-Landmann, S. et al. Syk- and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17. Nat. Immunol. 8, 630–638 (2007).

    Article  CAS  Google Scholar 

  13. Gringhuis, S.I. et al. Dectin-1 directs T helper cell differentiation by controlling noncanonical NF-κB activation through Raf-1 and Syk. Nat. Immunol. 10, 203–213 (2009).

    Article  CAS  Google Scholar 

  14. Ferwerda, B. et al. Human dectin-1 deficiency and mucocutaneous fungal infections. N. Engl. J. Med. 361, 1760–1767 (2009).

    Article  CAS  Google Scholar 

  15. Rogers, N.C. et al. Syk-dependent cytokine induction by Dectin-1 reveals a novel pattern recognition pathway for C type lectins. Immunity 22, 507–517 (2005).

    Article  CAS  Google Scholar 

  16. Rawlings, D.J., Sommer, K. & Moreno-Garcia, M.E. The CARMA1 signalosome links the signalling machinery of adaptive and innate immunity in lymphocytes. Nat. Rev. Immunol. 6, 799–812 (2006).

    Article  CAS  Google Scholar 

  17. Gringhuis, S.I. et al. Selective c-Rel activation via Malt1 controls anti-fungal TH-17 immunity by dectin-1 and dectin-2. PLoS Pathog. 7, e1001259 (2011).

    Article  CAS  Google Scholar 

  18. Netea, M.G. et al. IL-1β processing in host defense: beyond the inflammasomes. PLoS Pathog. 6, e1000661 (2010).

    Article  Google Scholar 

  19. Kayagaki, N. et al. Non-canonical inflammasome activation targets caspase-11. Nature 479, 117–121 (2011).

    Article  CAS  Google Scholar 

  20. Schroder, K. & Tschopp, J. The inflammasomes. Cell 140, 821–832 (2010).

    Article  CAS  Google Scholar 

  21. Poeck, H. et al. Recognition of RNA virus by RIG-I results in activation of CARD9 and inflammasome signaling for interleukin 1β production. Nat. Immunol. 11, 63–69 (2010).

    Article  CAS  Google Scholar 

  22. Schroder, K., Zhou, R. & Tschopp, J. The NLRP3 inflammasome: a sensor for metabolic danger? Science 327, 296–300 (2010).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  24. Gross, O. et al. Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence. Nature 459, 433–436 (2009).

    Article  CAS  Google Scholar 

  25. Saïd-Sadier, N., Padilla, E., Langsley, G. & Ojcius, D.M. Aspergillus fumigatus stimulates the NLRP3 inflammasome through a pathway requiring ROS production and the Syk tyrosine kinase. PLoS ONE 5, e10008 (2010).

    Article  Google Scholar 

  26. Hise, A.G. et al. An essential role for the NLRP3 inflammasome in host defense against the human fungal pathogen Candida albicans. Cell Host Microbe 5, 487–497 (2009).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  28. 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  Google Scholar 

  29. Maelfait, J. & Beyaert, R. Non-apoptotic functions of caspase-8. Biochem. Pharmacol. 76, 1365–1373 (2008).

    Article  CAS  Google Scholar 

  30. Oberst, A. & Green, D.R. It cuts both ways: reconciling the dual roles of caspase 8 in cell death and survival. Nat. Rev. Mol. Cell Biol. 12, 757–763 (2011).

    Article  CAS  Google Scholar 

  31. Kawadler, H., Gantz, M.A., Riley, J.L. & Yang, X. The paracaspase MALT1 controls caspase-8 activation during lymphocyte proliferation. Mol. Cell 31, 415–421 (2008).

    Article  CAS  Google Scholar 

  32. Thome, M. Multifunctional roles for MALT1 in T-cell activation. Nat. Rev. Immunol. 8, 495–500 (2008).

    Article  CAS  Google Scholar 

  33. Rebeaud, F. et al. The proteolytic activity of the paracaspase MALT1 is key in T cell activation. Nat. Immunol. 9, 272–281 (2008).

    Article  CAS  Google Scholar 

  34. Goddette, D.W. & Frieden, C. Actin polymerization. The mechanism of action of cytochalasin D. J. Biol. Chem. 261, 15974–15980 (1986).

    CAS  PubMed  Google Scholar 

  35. Hohl, T.M. et al. Aspergillus fumigatus triggers inflammatory responses by stage-specific β-glucan display. PLoS Pathog. 1, e30 (2005).

    Article  Google Scholar 

  36. Zenaro, E., Donini, M. & Dusi, S. Induction of Th1/Th17 immune response by Mycobacterium tuberculosis: role of dectin-1, mannose receptor, and DC-SIGN. J. Leukoc. Biol. 86, 1393–1401 (2009).

    Article  CAS  Google Scholar 

  37. Rothfuchs, A.G. et al. Dectin-1 interaction with Mycobacterium tuberculosis leads to enhanced IL-12p40 production by splenic dendritic cells. J. Immunol. 179, 3463–3471 (2007).

    Article  CAS  Google Scholar 

  38. van de Veerdonk, F.L. et al. Mycobacterium tuberculosis induces IL-17A responses through TLR4 and dectin-1 and is critically dependent on endogenous IL-1. J. Leukoc. Biol. 88, 227–232 (2010).

    Article  CAS  Google Scholar 

  39. Masumoto, J. et al. ASC is an activating adaptor for NF-κB and caspase-8-dependent apoptosis. Biochem. Biophys. Res. Commun. 303, 69–73 (2003).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  41. Glocker, E.O. et al. A homozygous CARD9 mutation in a family with susceptibility to fungal infections. N. Engl. J. Med. 361, 1727–1735 (2009).

    Article  CAS  Google Scholar 

  42. Bellocchio, S. et al. The contribution of the Toll-like/IL-1 receptor superfamily to innate and adaptive immunity to fungal pathogens in vivo. J. Immunol. 172, 3059–3069 (2004).

    Article  CAS  Google Scholar 

  43. Vonk, A. et al. Endogenous interleukin (IL)-1α and IL-1β are crucial for host defense against disseminated candidiasis. J. Infect. Dis. 193, 1419–1426 (2006).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  45. Fantuzzi, G. et al. Response to local inflammation of IL-1β-converting enzyme-deficient mice. J. Immunol. 158, 1818–1824 (1997).

    CAS  PubMed  Google Scholar 

  46. Geahlen, R.L. & McLaughlin, J.L. Piceatannol (3,4,3′,5′-tetrahydroxy-trans-stilbene) is a naturally occurring protein-tyrosine kinase inhibitor. Biochem. Biophys. Res. Commun. 165, 241–245 (1989).

    Article  CAS  Google Scholar 

  47. Nicholson, D.W. et al. Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature 376, 37–43 (1995).

    Article  CAS  Google Scholar 

  48. Garcia-Calvo, M. et al. Inhibition of human caspases by peptide-based and macromolecular inhibitors. J. Biol. Chem. 273, 32608–32613 (1998).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank J. Belisle (Colorado State University) for M. tuberculosis (as part of HHSN266200400091C (“Tuberculosis Vaccine Testing and Research Materials”) from the National Institute of Allergy and Infectious Diseases of the US National Institutes of Health); B. Appelmelk (VU Medical Center, Amsterdam) for M. bovis BCG; and J. Spencer (Colorado State University) for M. leprae. Supported by the Netherlands Organisation for Scientific Research (Netherlands Genomic Initiative 40-41009-98-8057 to S.I.G.; Vici 918.10.619 to T.B.H.G.) and the AIDS Foundation (2007036 to M.v.d.V.).

Author information

Authors and Affiliations

  1. Center of Infection and Immunity Amsterdam and Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    Sonja I Gringhuis, Tanja M Kaptein, Brigitte A Wevers, Michiel van der Vlist & Teunis B H Geijtenbeek

  2. Centraalbureau voor Schimmelcultures, Utrecht, The Netherlands

    Bart Theelen & Teun Boekhout

Authors
  1. Sonja I Gringhuis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tanja M Kaptein
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Brigitte A Wevers
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bart Theelen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Michiel van der Vlist
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Teun Boekhout
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Teunis B H Geijtenbeek
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.I.G. designed and supervised all aspects of this study, did and interpreted most experiments and prepared the manuscript; T.M.K. did fungi stimulations, enzyme-linked immunosorbent assay (ELISA) of cytokines, flow cytometry and assays of caspase-8 and internalization; B.A.W. did ELISA of cytokines; B.T. and T.B. prepared the fungal strains; M.v.d.V. did silencing experiments; and T.B.H.G. supervised all aspects of this study and prepared the manuscript.

Corresponding authors

Correspondence to Sonja I Gringhuis or Teunis B H Geijtenbeek.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–10 and Table 1 (PDF 1311 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gringhuis, S., Kaptein, T., Wevers, B. et al. Dectin-1 is an extracellular pathogen sensor for the induction and processing of IL-1β via a noncanonical caspase-8 inflammasome. Nat Immunol 13, 246–254 (2012). https://doi.org/10.1038/ni.2222

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.2222

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