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Gout-associated uric acid crystals activate the NALP3 inflammasome

Nature volume 440, pages 237–241 (2006)Cite this article

Abstract

Development of the acute and chronic inflammatory responses known as gout and pseudogout are associated with the deposition of monosodium urate (MSU) or calcium pyrophosphate dihydrate (CPPD) crystals, respectively, in joints and periarticular tissues. Although MSU crystals were first identified as the aetiological agent of gout in the eighteenth century1 and more recently as a ‘danger signal’ released from dying cells2, little is known about the molecular mechanisms underlying MSU- or CPPD-induced inflammation. Here we show that MSU and CPPD engage the caspase-1-activating NALP3 (also called cryopyrin) inflammasome, resulting in the production of active interleukin (IL)-1β and IL-18. Macrophages from mice deficient in various components of the inflammasome such as caspase-1, ASC and NALP3 are defective in crystal-induced IL-1β activation. Moreover, an impaired neutrophil influx is found in an in vivo model of crystal-induced peritonitis in inflammasome-deficient mice or mice deficient in the IL-1β receptor (IL-1R). These findings provide insight into the molecular processes underlying the inflammatory conditions of gout and pseudogout, and further support a pivotal role of the inflammasome in several autoinflammatory diseases.

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Figure 1: Monosodium urate (MSU) and calcium pyrophosphate dihydrate (CPPD) crystals activate IL-1β cleavage and release.
Figure 2: The NALP3 inflammasome is required for the maturation of IL-1β.
Figure 3: IL-1β maturation is an early event after MSU and CPPD stimulation, and is blocked by colchicine.
Figure 4: Role of the inflammasome in a mouse model of crystal-mediated peritonitis.

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Acknowledgements

We thank C. Mattmann for technical support and A. So, H. Everett, E. Meylan, M. Thome and P. Schneider for discussions and critical reading of the manuscript. We thank S. Mariathasan, V. M. Dixit, R. A. Flavell, M. Kopf and S. Akira for the gift of various knockout mice. This work was supported by grants from the Swiss National Science Foundation and the Commission of Technology and Innovation (CTI). V.P. is supported by a fellowship of the FRM (Fondation pour la Recherche Médicale); A.T. by a NCCR grant.

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  1. Department of Biochemistry, University of Lausanne, Chemin des Boveresses 155, 1066, Epalinges, Switzerland

    Fabio Martinon, Virginie Pétrilli, Annick Mayor, Aubry Tardivel & Jürg Tschopp

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  1. Fabio Martinon
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  2. Virginie Pétrilli
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Correspondence to Jürg Tschopp.

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Supplementary information

Supplementary Methods

This file contains additional details on the crystal preparation methods, and the reagents and mice used in this study. (DOC 80 kb)

Supplementary Figure Legends

Text to accompany the below Supplementary Figures. (DOC 25 kb)

Supplementary Figure 1

Gene targeting strategy for disruption of the mouse NALP3 gene. (PDF 46 kb)

Supplementary Figure 2

Monosodium urate crystals (MSU)-mediated activation of IL-1β occurs independently of the ATP-receptor P2X7. (PDF 296 kb)

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Martinon, F., Pétrilli, V., Mayor, A. et al. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440, 237–241 (2006). https://doi.org/10.1038/nature04516

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