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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 761-773 |
| Number of pages | 13 |
| Journal | Immunity |
| Volume | 45 |
| Issue number | 4 |
| DOIs | |
| State | Published - Oct 18 2016 |
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ASJC Scopus subject areas
- Immunology and Allergy
- Immunology
- Infectious Diseases
Cite this
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; Ćiković, 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.
In: Immunity, Vol. 45, No. 4, 18.10.2016, p. 761-773.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - K+ Efflux-Independent NLRP3 Inflammasome Activation by Small Molecules Targeting Mitochondria
AU - Groß, Christina J.
AU - Mishra, Ritu
AU - Schneider, Katharina S.
AU - Médard, Guillaume
AU - Wettmarshausen, Jennifer
AU - Dittlein, Daniela C.
AU - Shi, Hexin
AU - Gorka, Oliver
AU - Koenig, Paul Albert
AU - Fromm, Stephan
AU - Magnani, Giovanni
AU - Ćiković, Tamara
AU - Hartjes, Lara
AU - Smollich, Joachim
AU - Robertson, Avril A B
AU - Cooper, Matthew A.
AU - Schmidt-Supprian, Marc
AU - Schuster, Michael
AU - Schroder, Kate
AU - Broz, Petr
AU - Traidl-Hoffmann, Claudia
AU - Beutler, Bruce
AU - Kuster, Bernhard
AU - Ruland, Jürgen
AU - Schneider, Sabine
AU - Perocchi, Fabiana
AU - Groß, Olaf
PY - 2016/10/18
Y1 - 2016/10/18
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84994910645&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84994910645&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2016.08.010
DO - 10.1016/j.immuni.2016.08.010
M3 - Article
C2 - 27692612
AN - SCOPUS:84994910645
VL - 45
SP - 761
EP - 773
JO - Immunity
JF - Immunity
SN - 1074-7613
IS - 4
ER -