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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)
Verlagsversion Forschungsdaten DOI PMC
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Nalp3 Inflammasome; Immune Cells; Apoptosis; Inhibitor; Disease; Oxygen; Macrophages; Metabolism; Crystals; Death
ISSN (print) / ISBN 1074-7613
e-ISSN 1097-4180
Zeitschrift Immunity
Quellenangaben Band: 45, Heft: 4, Seiten: 761-773 Artikelnummer: , Supplement: ,
Verlag Cell Press
Verlagsort Cambridge, Mass.
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes and Obesity (IDO)
Institute of Environmental Medicine (IEM)