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K(+) Efflux-Independent NLRP3 Inflammasome Activation by Small Molecules Targeting Mitochondria

Groß, Christina J. and Mishra, Ritu and Schneider, Katharina S. and Médard, Guillaume and Wettmarshausen, Jennifer and Dittlein, Daniela C. and Shi, Hexin and Gorka, Oliver and Koenig, Paul-Albert and Fromm, Stephan and Magnani, Giovanni and Ćiković, Tamara and Hartjes, Lara and Smollich, Joachim and Robertson, Avril A. B. and Cooper, Matthew A. and Schmidt-Supprian, Marc and Schuster, Michael and Schroder, Kate and Broz, Petr and Traidl-Hoffmann, Claudia and Beutler, Bruce and Kuster, Bernhard and Ruland, Jürgen and Schneider, Sabine and Perocchi, Fabiana and Groß, Olaf. (2016) K(+) Efflux-Independent NLRP3 Inflammasome Activation by Small Molecules Targeting Mitochondria. Immunity, 45 (4). pp. 761-773.

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Official URL: http://edoc.unibas.ch/44508/

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Abstract

Imiquimod is a small-molecule ligand of Toll-like receptor-7 (TLR7) that is licensed for the treatment of viral infections and cancers of the skin. Imiquimod has TLR7-independent activities that are mechanistically unexplained, including NLRP3 inflammasome activation in myeloid cells and apoptosis induction in cancer cells. We investigated the mechanism of inflammasome activation by imiquimod and the related molecule CL097 and determined that K(+) efflux was dispensable for NLRP3 activation by these compounds. Imiquimod and CL097 inhibited the quinone oxidoreductases NQO2 and mitochondrial Complex I. This induced a burst of reactive oxygen species (ROS) and thiol oxidation, and led to NLRP3 activation via NEK7, a recently identified component of this inflammasome. Metabolic consequences of Complex I inhibition and endolysosomal effects of imiquimod might also contribute to NLRP3 activation. Our results reveal a K(+) efflux-independent mechanism for NLRP3 activation and identify targets of imiquimod that might be clinically relevant.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Former Organization Units Biozentrum > Infection Biology (Broz)
UniBasel Contributors:Broz, Petr
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Cell Press
ISSN:1074-7613
e-ISSN:1097-4180
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:26 Oct 2017 12:26
Deposited On:26 Oct 2017 12:26

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