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 Broz; Claudia Traidl-Hoffmann; Bruce Beutler; Bernhard Kuster; Jürgen Ruland; Sabine Schneider; Fabiana Perocchi; Olaf Groß

doi:10.1016/j.immuni.2016.08.010

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 journal › Article

94 Scopus citations

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 language	English (US)
Pages (from-to)	761-773
Number of pages	13
Journal	Immunity
Volume	45
Issue number	4
DOIs	https://doi.org/10.1016/j.immuni.2016.08.010
State	Published - Oct 18 2016

ASJC Scopus subject areas

Immunology and Allergy
Immunology
Infectious Diseases

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Groß, C. J., Mishra, R., Schneider, K. S., Médard, G., Wettmarshausen, J., Dittlein, D. C., Shi, H., Gorka, O., Koenig, P. A., Fromm, S., Magnani, G., Ćiković, T., Hartjes, L., Smollich, J., Robertson, A. A. B., Cooper, M. A., Schmidt-Supprian, M., Schuster, M., Schroder, K., ... 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 journal › Article

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, 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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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.",

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AU - Wettmarshausen, Jennifer

AU - Dittlein, Daniela C.

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AU - Cooper, Matthew A.

AU - Schmidt-Supprian, Marc

AU - Schuster, Michael

AU - Schroder, Kate

AU - Broz, Petr

AU - Traidl-Hoffmann, Claudia

AU - Beutler, Bruce

AU - Kuster, Bernhard

AU - Ruland, Jürgen

AU - Schneider, Sabine

AU - Perocchi, Fabiana

AU - Groß, Olaf

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N2 - 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.

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