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

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Serval ID
serval:BIB_DBC2755173A5
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Production externe
Title
K+ Efflux-Independent NLRP3 Inflammasome Activation by Small Molecules Targeting Mitochondria.
Journal
Immunity
Author(s)
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 AAB, Cooper M.A., Schmidt-Supprian M., Schuster M., Schroder K., Broz P., Traidl-Hoffmann C., Beutler B., Kuster B., Ruland J., Schneider S., Perocchi F., Groß O.
ISSN
1097-4180 (Electronic)
ISSN-L
1074-7613
Publication state
Published
Issued date
2016
Peer-reviewed
Oui
Volume
45
Number
4
Pages
761-773
Language
english
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.

Keywords
Animals, Electron Transport Complex I/metabolism, Inflammasomes/metabolism, Mice, Mitochondria/drug effects, Mitochondria/metabolism, NIMA-Related Kinases/metabolism, NLR Family, Pyrin Domain-Containing 3 Protein/metabolism, Potassium/metabolism, Quinone Reductases/metabolism, RNA, Small Nuclear/pharmacology, Reactive Oxygen Species/metabolism, Toll-Like Receptor 7/metabolism
DOI
10.1016/j.immuni.2016.08.010
Pubmed
27692612
Web of science
000389473200010
Create date
25/10/2017 11:05
Last modification date
20/08/2019 17:00
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