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Thioredoxin-interacting protein links oxidative stress to inflammasome activation

Nature Immunology volume 11, pages 136–140 (2010)Cite this article

Abstract

The NLRP3 inflammasome has a major role in regulating innate immunity. Deregulated inflammasome activity is associated with several inflammatory diseases, yet little is known about the signaling pathways that lead to its activation. Here we show that NLRP3 interacted with thioredoxin (TRX)-interacting protein (TXNIP), a protein linked to insulin resistance. Inflammasome activators such as uric acid crystals induced the dissociation of TXNIP from thioredoxin in a reactive oxygen species (ROS)-sensitive manner and allowed it to bind NLRP3. TXNIP deficiency impaired activation of the NLRP3 inflammasome and subsequent secretion of interleukin 1β (IL-1β). Akin to Txnip−/− mice, Nlrp3−/− mice showed improved glucose tolerance and insulin sensitivity. The participation of TXNIP in the NLRP3 inflammasome activation may provide a mechanistic link to the observed involvement of IL-1β in the pathogenesis of type 2 diabetes.

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Figure 1: TXNIP binds to NLRP3.
Figure 2: ROS induce the dissociation of TXNIP from TRX and binding to NLRP3.
Figure 3: The kinetics of ROS production, the dissociation of TXNIP from TRX and the association of TXNIP with NLRP3 in THP-1 cells.
Figure 4: TXNIP is essential for activation of the NLRP3 inflammasome.
Figure 5: TXNIP is essential for activation of the NLRP3 inflammasome in vivo.
Figure 6: Expression of TXNIP is induced by glucose.
Figure 7: TXNIP and NLRP3 are linked to the secretion of IL-1β from islet cells.
Figure 8: NLRP3 deficiency affects glucose homeostasis.

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Acknowledgements

We thank P. Vandenabeele (Ghent University) for antibody to mouse caspase-1 (p20); V. Dixit (Genentech) for Ipaf−/− mice; R.V. Bruggen (Free University Amsterdam) for S. typhimurium; R. Solari (Glaxo) for antibody to mouse IL-1β; M. Joffraud for technical help; and K. Schroder, C. Dostert and O. Gross for reading the manuscript. Supported by the Swiss National Science Foundation, MUGEN and the Swiss National Center of Competence in Research for Molecular Oncology (A.T.).

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Authors and Affiliations

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

    Rongbin Zhou, Aubry Tardivel & Jürg Tschopp

  2. Center of Integrative Genomics, University of Lausanne, Epalinges, Switzerland

    Bernard Thorens

  3. Korea Research Institute of Bioscience and Biotechnology, Yusong, Taejon, Republic of Korea

    Inpyo Choi

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  1. Rongbin Zhou
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  2. Aubry Tardivel
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Contributions

R.Z. and J.T. designed the study and wrote the manuscript; R.Z. and A.T. did experiments; I.C. provided mice; and B.T. provided technical support and conceptual advice.

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Correspondence to Jürg Tschopp.

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Zhou, R., Tardivel, A., Thorens, B. et al. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat Immunol 11, 136–140 (2010). https://doi.org/10.1038/ni.1831

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