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

被引：499

作者：

Gross, Christina J. ^{[1
]}

Mishra, Ritu ^{[1
]}

Schneider, Katharina S. ^{[1
]}

Medard, Guillaume ^{[2
]}

Wettmarshausen, Jennifer ^{[8
,9
]}

Dittlein, Daniela C. ^{[7
,8
]}

Shi, Hexin ^{[11
]}

Gorka, Oliver ^{[1
]}

Koenig, Paul-Albert ^{[1
]}

Fromm, Stephan ^{[3
]}

Magnani, Giovanni ^{[1
]}

Cikovic, Tamara ^{[1
]}

Hartjes, Lara ^{[1
]}

Smollich, Joachim ^{[1
]}

Robertson, Avril A. B. ^{[12
]}

Cooper, Matthew A. ^{[12
]}

Schmidt-Supprian, Marc ^{[4
,5
]}

Schuster, Michael ^{[3
]}

Schroder, Kate ^{[12
]}

Broz, Petr ^{[13
]}

Traidl-Hoffmann, Claudia ^{[7
,8
]}

Beutler, Bruce ^{[11
]}

Kuster, Bernhard ^{[2
,10
]}

Ruland, Juergen ^{[1
,5
]}

Schneider, Sabine ^{[6
,10
]}

Perocchi, Fabiana ^{[8
,9
]}

Gross, Olaf ^{[1
,5
]}

机构：

[1] TUM, Klinikum Rechts Isar, Inst Klin Chem & Pathobiochem, D-81675 Munich, Germany

[2] TUM, Chair Prote & Bioanalyt, D-85354 Freising Weihenstephan, Germany

[3] TUM, Dept Chem, Fachgrp Analyt Chem, D-85748 Garching, Germany

[4] TUM, Klinikum Rechts Isar, Dept Hematol & Oncol, D-81675 Munich, Germany

[5] TUM, TranslaTUM Zent Inst Translat Krebsforsch, D-81675 Munich, Germany

[6] TUM, Dept Chem, D-85748 Garching, Germany

[7] TUM, UNIKA T, Chair & Inst Environm Med, D-86156 Augsburg, Germany

[8] Helmholtz Zentrum Munchen, D-85764 Neuherberg, Germany

[9] Ludwig Maximilians Univ Munchen, Dept Biochem, Genzentrum, D-81377 Munich, Germany

[10] CIPSM, D-81377 Munich, Germany

[11] Univ Texas Southwestern Med Ctr Dallas, Ctr Genet Host Def, Dallas, TX 75390 USA

[12] Univ Queensland, Inst Mol Biosci, Brisbane, Qld 4067, Australia

[13] Univ Basel, Biozentrum, Focal Area Infect Biol, CH-4003 Basel, Switzerland

来源：

IMMUNITY | 2016年 / 45卷 / 04期

基金：

英国医学研究理事会; 加拿大自然科学与工程研究理事会; 澳大利亚国家健康与医学研究理事会; 欧洲研究理事会; 澳大利亚研究理事会;

关键词：

IMMUNE CELLS; INHIBITOR; APOPTOSIS; OXYGEN; METABOLISM; CRYSTALS;

D O I：

10.1016/j.immuni.2016.08.010

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

071005 [微生物学]; 100108 [医学免疫学];

摘要：

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 imiquimodmight 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.

引用

页码：761 / 773

页数：13

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