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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

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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.

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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.

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  • 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.

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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.).

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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

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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.

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Correspondence to Sonja I Gringhuis or Teunis B H Geijtenbeek.

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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

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