Mitochondrial cardiolipin is required for Nlrp3 inflammasome activation

Shankar S. Iyer, Qiong He, John R. Janczy, Eric I. Elliott, Zhenyu Zhong, Alicia K. Olivier, Jeffrey J. Sadler, Vickie Knepper-Adrian, Renzhi Han, Liang Qiao, Stephanie C. Eisenbarth, William M. Nauseef, Suzanne L. Cassel, Fayyaz S. Sutterwala

Research output: Contribution to journalArticle

333 Scopus citations

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 themitochondrial lipid cardiolipin. Cardiolipin bound toNlrp3 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.

Original languageEnglish (US)
Pages (from-to)311-323
Number of pages13
JournalImmunity
Volume39
Issue number2
DOIs
StatePublished - Aug 22 2013

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Cite this

Iyer, S. S., He, Q., Janczy, J. R., Elliott, E. I., Zhong, Z., Olivier, A. K., Sadler, J. J., Knepper-Adrian, V., Han, R., Qiao, L., Eisenbarth, S. C., Nauseef, W. M., Cassel, S. L., & Sutterwala, F. S. (2013). Mitochondrial cardiolipin is required for Nlrp3 inflammasome activation. Immunity, 39(2), 311-323. https://doi.org/10.1016/j.immuni.2013.08.001