期刊
IMMUNITY
卷 39, 期 2, 页码 311-323出版社
CELL PRESS
DOI: 10.1016/j.immuni.2013.08.001
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类别
资金
- National Institutes of Health [R01 AI087630, K08 AI067736, R01 AR064241, R01 HL116546, T32 AI007485]
- American Heart Association Scientist Development Grant [10SDG4140138]
- Muscular Dystrophy Association [MDA171667]
- Asthma and Allergy Foundation of America fellowship
- Edward Mallinckrodt, Jr. Foundation scholarship
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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