Linezolid mediated NLRP3 inflammasome activation is independent of reactive oxygen species (ROS)

Activation of the Nlrp3 inflammasome has been shown in response to numerous activators; we show that antibiotic linezolid results in both the Nlrp3-dependent in vitro release of the proinflammatory cytokine IL-1β and in vivo neutrophilic influx following its intraperitoneal administration. Clinical use of linezolid is commonly limited by hematologic side effects; herein we also show Nlrp3-deficiency protected animals against linezolid-induced effects on the bone marrow. Importantly, all previously described activators of the Nlrp3 inflammasome have required the generation of reactive oxygen species (ROS), recently shown to be of mitochondrial origin, for activation. Linezolid is however unique amongst Nlrp3 agonists in that its ability to activate the Nlrp3 inflammasome is independent of ROS. This novel finding reveals that ROS generation is not the canonical activator of Nlrp3 but rather an intermediary step leading to the mitochondrial perturbation that is tied to Nlrp3 inflammasome activation.

Iyer SS, He Q, Janczy JR, Elliott EI, Zhong Z, Olivier AK, Sadler JJ, Knepper-Adrian V, Han R, Qiao L, Eisenbarth SC, Nauseef WM, Cassel SL, Sutterwala FS. Mitochondrial cardiolipin is required for Nlrp3 inflammasome activation. Immunity. 2013 Aug 22;39(2):311-23. doi: 10.1016/j.immuni.2013.08.001. Epub 2013 Aug 15. PubMed PMID: 23954133; PubMed Central PMCID: PMC3779285.