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

Christina J. Groß, Ritu Mishra, Katharina S. Schneider, Guillaume Médard, Jennifer Wettmarshausen, Daniela C. Dittlein, Hexin Shi, Oliver Gorka, Paul Albert Koenig, Stephan Fromm, Giovanni Magnani, Tamara Ćiković, Lara Hartjes, Joachim Smollich, Avril A B Robertson, Matthew A. Cooper, Marc Schmidt-Supprian, Michael Schuster, Kate Schroder, Petr BrozClaudia Traidl-Hoffmann, Bruce Beutler, Bernhard Kuster, Jürgen Ruland, Sabine Schneider, Fabiana Perocchi, Olaf Groß

Research output: Contribution to journalArticle

72 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)761-773
Number of pages13
JournalImmunity
Volume45
Issue number4
DOIs
StatePublished - Oct 18 2016

Fingerprint

imiquimod
Inflammasomes
Mitochondria
Toll-Like Receptor 7
Skin Neoplasms
Virus Diseases
Myeloid Cells
Sulfhydryl Compounds
Reactive Oxygen Species
Oxidoreductases
Apoptosis
Ligands

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Cite this

Groß, C. J., Mishra, R., Schneider, K. S., Médard, G., Wettmarshausen, J., Dittlein, D. C., ... Groß, O. (2016). K+ Efflux-Independent NLRP3 Inflammasome Activation by Small Molecules Targeting Mitochondria. Immunity, 45(4), 761-773. https://doi.org/10.1016/j.immuni.2016.08.010

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

In: Immunity, Vol. 45, No. 4, 18.10.2016, p. 761-773.

Research output: Contribution to journalArticle

Groß, CJ, Mishra, R, Schneider, KS, Médard, G, Wettmarshausen, J, Dittlein, DC, Shi, H, Gorka, O, Koenig, PA, Fromm, S, Magnani, G, Ćiković, T, Hartjes, L, Smollich, J, Robertson, AAB, Cooper, MA, Schmidt-Supprian, M, Schuster, M, Schroder, K, Broz, P, Traidl-Hoffmann, C, Beutler, B, Kuster, B, Ruland, J, Schneider, S, Perocchi, F & Groß, O 2016, 'K+ Efflux-Independent NLRP3 Inflammasome Activation by Small Molecules Targeting Mitochondria', Immunity, vol. 45, no. 4, pp. 761-773. https://doi.org/10.1016/j.immuni.2016.08.010
Groß CJ, Mishra R, Schneider KS, Médard G, Wettmarshausen J, Dittlein DC et al. K+ Efflux-Independent NLRP3 Inflammasome Activation by Small Molecules Targeting Mitochondria. Immunity. 2016 Oct 18;45(4):761-773. https://doi.org/10.1016/j.immuni.2016.08.010
Groß, Christina J. ; Mishra, Ritu ; Schneider, Katharina S. ; Médard, Guillaume ; Wettmarshausen, Jennifer ; Dittlein, Daniela C. ; Shi, Hexin ; Gorka, Oliver ; Koenig, Paul Albert ; Fromm, Stephan ; Magnani, Giovanni ; Ćiković, Tamara ; Hartjes, Lara ; Smollich, Joachim ; Robertson, Avril A B ; Cooper, Matthew A. ; Schmidt-Supprian, Marc ; Schuster, Michael ; Schroder, Kate ; Broz, Petr ; Traidl-Hoffmann, Claudia ; Beutler, Bruce ; Kuster, Bernhard ; Ruland, Jürgen ; Schneider, Sabine ; Perocchi, Fabiana ; Groß, Olaf. / K+ Efflux-Independent NLRP3 Inflammasome Activation by Small Molecules Targeting Mitochondria. In: Immunity. 2016 ; Vol. 45, No. 4. pp. 761-773.
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