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

Publikation: Beitrag in Fachzeitschrift › Artikel › Begutachtung

358 Zitate (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.

Originalsprache	Englisch
Seiten (von - bis)	761-773
Seitenumfang	13
Fachzeitschrift	Immunity
Jahrgang	45
Ausgabenummer	4
DOIs	https://doi.org/10.1016/j.immuni.2016.08.010
Publikationsstatus	Veröffentlicht - 18 Okt. 2016

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10.1016/j.immuni.2016.08.010

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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

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title = "K+ Efflux-Independent NLRP3 Inflammasome Activation by Small Molecules Targeting Mitochondria",

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.",

author = "Gro{\ss}, {Christina J.} and Ritu Mishra and Schneider, {Katharina S.} and Guillaume M{\'e}dard and Jennifer Wettmarshausen and Dittlein, {Daniela C.} and Hexin Shi and Oliver Gorka and Koenig, {Paul Albert} and Stephan Fromm and Giovanni Magnani and Tamara {\'C}ikovi{\'c} and Lara Hartjes and Joachim Smollich and Robertson, {Avril A.B.} and Cooper, {Matthew A.} and Marc Schmidt-Supprian and Michael Schuster and Kate Schroder and Petr Broz and Claudia Traidl-Hoffmann and Bruce Beutler and Bernhard Kuster and J{\"u}rgen Ruland and Sabine Schneider and Fabiana Perocchi and Olaf Gro{\ss}",

note = "Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",

year = "2016",

month = oct,

day = "18",

doi = "10.1016/j.immuni.2016.08.010",

language = "English",

volume = "45",

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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, Jg. 45, Nr. 4, S. 761-773. https://doi.org/10.1016/j.immuni.2016.08.010

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T1 - K+ Efflux-Independent NLRP3 Inflammasome Activation by Small Molecules Targeting Mitochondria

AU - Groß, Christina J.

AU - Mishra, Ritu

AU - Schneider, Katharina S.

AU - Médard, Guillaume

AU - Wettmarshausen, Jennifer

AU - Dittlein, Daniela C.

AU - Shi, Hexin

AU - Gorka, Oliver

AU - Koenig, Paul Albert

AU - Fromm, Stephan

AU - Magnani, Giovanni

AU - Ćiković, Tamara

AU - Hartjes, Lara

AU - Smollich, Joachim

AU - Robertson, Avril A.B.

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

PY - 2016/10/18

Y1 - 2016/10/18

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.

AB - 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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DO - 10.1016/j.immuni.2016.08.010

M3 - Article

C2 - 27692612

AN - SCOPUS:84994910645

SN - 1074-7613

VL - 45

SP - 761

EP - 773

JO - Immunity

JF - Immunity

IS - 4