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Immunity. 2013 Aug 22;39(2):311-323. doi: 10.1016/j.immuni.2013.08.001. Epub 2013 Aug 15.

Mitochondrial cardiolipin is required for Nlrp3 inflammasome activation.

Author information

1
Inflammation Program, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
2
Graduate Program in Immunology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
3
Graduate Program in Molecular and Cellular Biology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
4
Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA.
5
Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
6
the Department of Cell & Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA.
7
Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
8
Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
9
Veterans Affairs Medical Center, Iowa City, IA 52241, USA.
#
Contributed equally

Abstract

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.

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PMID:
23954133
PMCID:
PMC3779285
DOI:
10.1016/j.immuni.2013.08.001
[Indexed for MEDLINE]
Free PMC Article
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