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Molecular identification of a danger signal that alerts the immune system to dying cells

Nature volume 425, pages 516–521 (2003)Cite this article

Abstract

In infections, microbial components provide signals that alert the immune system to danger and promote the generation of immunity1,2. In the absence of such signals, there is often no immune response or tolerance may develop. This has led to the concept that the immune system responds only to antigens perceived to be associated with a dangerous situation such as infection3,4. Danger signals are thought to act by stimulating dendritic cells to mature so that they can present foreign antigens and stimulate T lymphocytes2,5,6,7. Dying mammalian cells have also been found to release danger signals of unknown identity8,9,10,11. Here we show that uric acid is a principal endogenous danger signal released from injured cells. Uric acid stimulates dendritic cell maturation and, when co-injected with antigen in vivo, significantly enhances the generation of responses from CD8+ T cells. Eliminating uric acid in vivo inhibits the immune response to antigens associated with injured cells, but not to antigens presented by activated dendritic cells. Our findings provide a molecular link between cell injury and immunity and have important implications for vaccines, autoimmunity and inflammation.

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Figure 1: Purification of the LMW endogenous adjuvant from cytosol.
Figure 2: Molecular identification of the LMW endogenous adjuvant.
Figure 3: Uric acid has adjuvant activity in vivo and its concentrations increase in injured cells.
Figure 4: Eliminating uric acid in vivo inhibits adjuvant activity from injured cells.
Figure 5: MSU crystals rapidly activate dendritic cells.
Figure 6: Specificity of dendritic cell activation by MSU crystals.

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Acknowledgements

We thank J. Sodrosky, J. Berzofsky, N. Sato, Y. Takeda and T. Vedvick for reagents; B. Zhang, P. Furcinitti and B. Kobertz for advice and technical assistance; and L. Stern and I. York for critically reviewing the manuscript. The work was supported by NIH grants to K.L.R. Y.S. was also supported by a grant from the Pittsfield TB association.

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Authors and Affiliations

  1. Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, 01655, USA

    Yan Shi & Kenneth L. Rock

  2. Proteomics and Mass Spectrometry Facility, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts, 01655, USA

    James E. Evans

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Correspondence to Kenneth L. Rock.

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Shi, Y., Evans, J. & Rock, K. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 425, 516–521 (2003). https://doi.org/10.1038/nature01991

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