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A role for mitochondria in NLRP3 inflammasome activation

Nature volume 469, pages 221225 (13 January 2011) | Download Citation

  • A Corrigendum to this article was published on 15 June 2011

This article has been updated

Abstract

An inflammatory response initiated by the NLRP3 inflammasome is triggered by a variety of situations of host ‘danger’, including infection and metabolic dysregulation1,2. Previous studies suggested that NLRP3 inflammasome activity is negatively regulated by autophagy and positively regulated by reactive oxygen species (ROS) derived from an uncharacterized organelle. Here we show that mitophagy/autophagy blockade leads to the accumulation of damaged, ROS-generating mitochondria, and this in turn activates the NLRP3 inflammasome. Resting NLRP3 localizes to endoplasmic reticulum structures, whereas on inflammasome activation both NLRP3 and its adaptor ASC redistribute to the perinuclear space where they co-localize with endoplasmic reticulum and mitochondria organelle clusters. Notably, both ROS generation and inflammasome activation are suppressed when mitochondrial activity is dysregulated by inhibition of the voltage-dependent anion channel. This indicates that NLRP3 inflammasome senses mitochondrial dysfunction and may explain the frequent association of mitochondrial damage with inflammatory diseases.

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Change history

  • 15 June 2011

    Some figure citations have been corrected. This correction was made on 15 June 2011.

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Acknowledgements

This study was supported by grants of the Swiss National Science Foundation and by the Institute for Arthritis Research. A.S.Y. is a recipient of a stipend of the DFG. We would like to thank K. Schroder, C. Thomas and J. Vince for critical reading of the manuscript and G. W. Knott, EPFL, Lausanne, for help in collecting electron micrographs.

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Affiliations

  1. Department of Biochemistry, Center of Immunity and Infection, University of Lausanne, Chemin des Boveresses 155, CH-1066 Epalinges, Switzerland

    • Rongbin Zhou
    • , Amir S. Yazdi
    • , Philippe Menu
    •  & Jürg Tschopp

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Contributions

R.Z., A.S.Y. and P.M. devised and performed the experiments. J.T. supervised the work.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jürg Tschopp.

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https://doi.org/10.1038/nature09663

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