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The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response

Nature volume 452, pages 103–107 (2008)Cite this article

Abstract

The innate immune system recognizes nucleic acids during infection and tissue damage. Whereas viral RNA is detected by endosomal toll-like receptors (TLR3, TLR7, TLR8) and cytoplasmic RIG-I and MDA5, endosomal TLR9 and cytoplasmic DAI bind DNA1, resulting in the activation of nuclear factor-κB and interferon regulatory factor transcription factors. However, viruses also trigger pro-inflammatory responses2, which remain poorly defined. Here we show that internalized adenoviral DNA induces maturation of pro-interleukin-1β in macrophages, which is dependent on NALP3 and ASC, components of the innate cytosolic molecular complex termed the inflammasome. Correspondingly, NALP3- and ASC-deficient mice display reduced innate inflammatory responses to adenovirus particles. Inflammasome activation also occurs as a result of transfected cytosolic bacterial, viral and mammalian (host) DNA, but in this case sensing is dependent on ASC but not NALP3. The DNA-sensing pro-inflammatory pathway functions independently of TLRs and interferon regulatory factors. Thus, in addition to viral and bacterial components or danger signals in general, inflammasomes sense potentially dangerous cytoplasmic DNA, strengthening their central role in innate immunity.

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Figure 1: Adenovirus infection activates IL-1β processing and secretion.
Figure 2: Role of viral and non-viral DNA in IL-1β activation.
Figure 3: Role of NALP3 and ASC in adenovirus and DNA activation of IL-1β.
Figure 4: Role of NALP3 in adenovirus-vector-induced inflammation in vivo.

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Acknowledgements

This work was supported by the Alberta Heritage Foundation for Medical Research, operating and group grants from the Canadian Institutes for Health Research, the Swiss Committee for Technology and Innovation and MUGEN. D.A.M. is the recipient of an AHFMR Scholar Award; A.K.Z. is the recipient of a Heart and Stroke Foundation of Canada Studentship; V.P. is the recipient of a Marie Curie training award. We thank R. Castillo for technical assistance, V. Dixit, A. Trumpp and S. Akira for knockout mice and P. Vandenabeele for the caspase-1 antibody.

Author Contributions D.A.M., V.P., A.K.Z., L.R.W., S.A.C., P.J.R. and R.J.P. conceived the research and conducted the experiments. J.T. oversaw the whole project.

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Author notes

  1. Daniel A. Muruve and Virginie Pétrilli: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine,,

    Daniel A. Muruve, Lindsay R. White & Sharon A. Clark

  2. Biochemistry and Molecular Biology, University of Calgary, Alberta T2N 4N1, Canada,

    Anne K. Zaiss

  3. Department of Biochemistry, University of Lausanne, Epalinges, Switzerland

    Virginie Pétrilli & Jurg Tschopp

  4. Molecular Medicine Program, Ottawa Health Research Institute, Ottawa, Ontario K1Y 4E9, Canada,

    P. Joel Ross & Robin J. Parks

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Correspondence to Jurg Tschopp.

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Muruve, D., Pétrilli, V., Zaiss, A. et al. The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response. Nature 452, 103–107 (2008). https://doi.org/10.1038/nature06664

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