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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; Cikovic, 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.
Afiliación
  • Groß CJ; Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München (TUM), 81675 Munich, Germany.
  • Mishra R; Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München (TUM), 81675 Munich, Germany.
  • Schneider KS; Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München (TUM), 81675 Munich, Germany.
  • Médard G; Chair of Proteomics and Bioanalytics, TUM, 85354 Freising, Germany.
  • Wettmarshausen J; Genzentrum, Department of Biochemistry, Ludwig-Maximilians-Universität München, 81377 Munich, and Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
  • Dittlein DC; Chair and Institute of Environmental Medicine, UNIKA-T, TUM, 86156 Augsburg, and Helmholtz Zentrum München, 85764 Neuherberg, Germany.
  • Shi H; Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Gorka O; Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München (TUM), 81675 Munich, Germany.
  • Koenig PA; Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München (TUM), 81675 Munich, Germany.
  • Fromm S; Fachgruppe Analytische Chemie, Department of Chemistry, TUM, 85748 Garching, Germany.
  • Magnani G; Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München (TUM), 81675 Munich, Germany.
  • Cikovic T; Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München (TUM), 81675 Munich, Germany.
  • Hartjes L; Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München (TUM), 81675 Munich, Germany.
  • Smollich J; Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München (TUM), 81675 Munich, Germany.
  • Robertson AAB; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4067, Australia.
  • Cooper MA; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4067, Australia.
  • Schmidt-Supprian M; Department of Hematology and Oncology, Klinikum rechts der Isar, TUM, 81675 Munich, Germany; TranslaTUM: Zentralinstitut für translationale Krebsforschung, TUM, 81675 Munich, Germany.
  • Schuster M; Fachgruppe Analytische Chemie, Department of Chemistry, TUM, 85748 Garching, Germany.
  • Schroder K; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4067, Australia.
  • Broz P; Focal Area Infection Biology, Biozentrum, University of Basel, 4003 Basel, Switzerland.
  • Traidl-Hoffmann C; Chair and Institute of Environmental Medicine, UNIKA-T, TUM, 86156 Augsburg, and Helmholtz Zentrum München, 85764 Neuherberg, Germany.
  • Beutler B; Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Kuster B; Chair of Proteomics and Bioanalytics, TUM, 85354 Freising, Germany; Center for Integrated Protein Science Munich (CIPSM), 81377 Munich, Germany.
  • Ruland J; Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München (TUM), 81675 Munich, Germany; TranslaTUM: Zentralinstitut für translationale Krebsforschung, TUM, 81675 Munich, Germany.
  • Schneider S; Department of Chemistry, TUM, 85748 Garching, Germany; Center for Integrated Protein Science Munich (CIPSM), 81377 Munich, Germany.
  • Perocchi F; Genzentrum, Department of Biochemistry, Ludwig-Maximilians-Universität München, 81377 Munich, and Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
  • Groß O; Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München (TUM), 81675 Munich, Germany; TranslaTUM: Zentralinstitut für translationale Krebsforschung, TUM, 81675 Munich, Germany. Electronic address: olaf.gross@tum.de.
Immunity ; 45(4): 761-773, 2016 10 18.
Article en En | MEDLINE | ID: mdl-27692612
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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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Potasio / ARN Nuclear Pequeño / Inflamasomas / Proteína con Dominio Pirina 3 de la Familia NLR / Mitocondrias Límite: Animals Idioma: En Revista: Immunity Asunto de la revista: ALERGIA E IMUNOLOGIA Año: 2016 Tipo del documento: Article País de afiliación: Alemania
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Potasio / ARN Nuclear Pequeño / Inflamasomas / Proteína con Dominio Pirina 3 de la Familia NLR / Mitocondrias Límite: Animals Idioma: En Revista: Immunity Asunto de la revista: ALERGIA E IMUNOLOGIA Año: 2016 Tipo del documento: Article País de afiliación: Alemania