TY - JOUR
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
N1 - Funding Information:
The authors thank Susanne Weiß, Valentin Höfl, Tanja Ruff, Markus Utzt, Michaela Glos, Sandra Reuwand, and Beatrix Lunk for technical assistance, and Stefan Bauer, Hubertus Hochrein, Thomas Korn, Anne Krug, Fiona Müllner, Peter Luppa, Klaus Heger, Tobias Madl, Jean Boutin, and Holger Prokisch for helpful discussions. Thorsten Buch and Philipp Yu provided bone marrow from TLR7 −/− and Unc93b1 3d/3d mice, respectively. Paul Schumacker provided adenovirus encoding organelle-targeted roGFP2, Laura Trovo and Thomas Misgeld helped setting up the ratiometric ROS measurement, and Deepak Ramanujam and Stefan Engelhardt assisted with adenovirus amplification. The SLS and ESRF provided access and assistance with X-ray crystallography. This work was supported by a postgraduate scholarship from the Natural Sciences and Engineering Research Council of Canada (to C.J.G.), a TUM Graduate School stipend (to K.S.S.), a post-doctoral fellowship of the TUM University Foundation (to P.A.K.), the international doctoral program “i-Target: Immunotargeting in Cancer,” funded by the Elite Network of Bavaria (to L.H.), a National Health and Medical Research Council (NHMRC) Project Grant ( 1086786 , to M.A.C. and K.S.), an NHMRC Fellowship ( 1059354 , to AABR), an Australian Research Council Future Fellowship ( FT130100361 , to K.S.), the Queensland Smart Futures Fund (to K.S.), the Christine Kühne Center for Allergy Research and Education (to C.T.-H.), the Helmholtz Alliance Preclinical Comprehensive Cancer Center (PCCC, to J.R.), the Deutsche Forschungsgemeinschaft (DFG, grants SFB 1054 and RU 695/6-1 , to J.R.), the German Cancer Consortium (DKTK, to J.R.), the German Center for Infection Research (DZIF, to J.R.), the DFG and the excellence cluster CIPSM and Fonds der chemischen Industrie (to S.S.), the DFG under the Emmy Noether Programme ( PE 2053/1-1 , to F.P.), the European Research Council (ERC) under the European Union’s Seventh Framework Programme by an ERC Advanced Grant (grant agreement No. 322865 , to J.R.) and an ERC Starting Grant (grant agreement No. 337689 , to O. Groß), and the Bavarian Ministry of Sciences, Research and the Arts , in the Framework of the Bavarian Molecular Biosystems Research Network (BioSysNet, to O. Groß).
Publisher Copyright:
© 2016 Elsevier Inc.
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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U2 - 10.1016/j.immuni.2016.08.010
DO - 10.1016/j.immuni.2016.08.010
M3 - Article
C2 - 27692612
AN - SCOPUS:84994910645
VL - 45
SP - 761
EP - 773
JO - Immunity
JF - Immunity
SN - 1074-7613
IS - 4
ER -