Mitochondrial Cardiolipin Is Required for Nlrp3 Inflammasome Activation

Nlrp3 inflammasome activation occurs in response to numerous agonists but the specific mechanism by which this takes place remains unclear. All previously evaluated activators of the Nlrp3 inflammasome induce the generation of mitochondrial reactive oxygen species (ROS), suggesting a model in which...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Immunity (Cambridge, Mass.) Mass.), 2013-08, Vol.39 (2), p.311-323
Hauptverfasser: Iyer, Shankar S., He, Qiong, Janczy, John R., Elliott, Eric I., Zhong, Zhenyu, Olivier, Alicia K., Sadler, Jeffrey J., Knepper-Adrian, Vickie, Han, Renzhi, Qiao, Liang, Eisenbarth, Stephanie C., Nauseef, William M., Cassel, Suzanne L., Sutterwala, Fayyaz S.
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung:Nlrp3 inflammasome activation occurs in response to numerous agonists but the specific mechanism by which this takes place remains unclear. All previously evaluated activators of the Nlrp3 inflammasome induce the generation of mitochondrial reactive oxygen species (ROS), suggesting a model in which ROS is a required upstream mediator of Nlrp3 inflammasome activation. Here we have identified the oxazolidinone antibiotic linezolid as a Nlrp3 agonist that activates the Nlrp3 inflammasome independently of ROS. The pathways for ROS-dependent and ROS-independent Nlrp3 activation converged upon mitochondrial dysfunction and specifically the mitochondrial lipid cardiolipin. Cardiolipin bound to Nlrp3 directly and interference with cardiolipin synthesis specifically inhibited Nlrp3 inflammasome activation. Together these data suggest that mitochondria play a critical role in the activation of the Nlrp3 inflammasome through the direct binding of Nlrp3 to cardiolipin. [Display omitted] •Nlrp3 inflammasome activation contributes to linezolid-induced in vivo toxicity•Mitochondrial ROS is dispensable for linezolid-induced inflammasome activation•Mitochondrial dysfunction is a prerequisite for Nlrp3 inflammasome activation•Cardiolipin binds to Nlrp3 and is required for Nlrp3 inflammasome activation
ISSN:1074-7613
1097-4180
DOI:10.1016/j.immuni.2013.08.001