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Groß, C.* ; Mishra, R.* ; Schneider, K.* ; Médard, G.* ; Wettmarshausen, J.* ; Dittlein, D. ; Shih, H.* ; Gorka, O.* ; König, P.* ; Fromm, S.* ; Magnani, G.* ; Cikovic, T.* ; Hartjes, L.* ; Smollich, J.* ; Robertson, A.A.B.* ; 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.*

K+ efflux-independent NLRP3 inflammasome activation by small molecules targeting mitochondria.

Immunity 45, 761-773 (2016)
Publ. Version/Full Text Research data DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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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Publication type Article: Journal article
Document type Scientific Article
Keywords Nalp3 Inflammasome; Immune Cells; Apoptosis; Inhibitor; Disease; Oxygen; Macrophages; Metabolism; Crystals; Death
Language english
Publication Year 2016
HGF-reported in Year 2016
ISSN (print) / ISBN 1074-7613
e-ISSN 1097-4180
Journal Immunity
Quellenangaben Volume: 45, Issue: 4, Pages: 761-773 Article Number: , Supplement: ,
Publisher Cell Press
Publishing Place Cambridge, Mass.
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Obesity (IDO)
Institute of Environmental Medicine (IEM)
POF-Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
30202 - Environmental Health
Research field(s) Genetics and Epidemiology
Allergy
PSP Element(s) G-553000-001
G-503400-001
DOI 10.1016/j.immuni.2016.08.010
WOS ID WOS:000389473200010
Scopus ID 84994910645
PubMed ID 27692612
Erfassungsdatum 2016-10-17
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