Mechanisms for activation and inhibition of inflammasomes

Abstract

NLRP3 inflammasome activation occurs in response to numerous agonists, but the specific mechanism by which activation occurs remains unclear. Virtually every agonist evaluated induces the generation of mitochondrial ROS, with the notable exception of the oxazolidinone antibiotic linezolid. Several studies have provided evidence that both ROS-dependent and ROS-independent NLRP3 activation converge upon mitochondrial dysfunction. Previous work in our lab has shown that NLRP3 specifically binds the mitochondrial lipid cardiolipin. Here we show that interference with cardiolipin synthesis specifically inhibits NLRP3 inflammasome activation. We further show that cardiolipin is sufficient, in a broken cell system, to activate caspase-1. 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. Introduction The NLRP3 inflammasome is a multi-protein complex consisting of the NLR family member NLRP3, the adaptor protein ASC, and the cysteine protease caspase-1. The NLRP3 inflammasome can activate caspase-1 in response to cellular danger, resulting in the processing and secretion of the proinflammatory cytokines IL-1β and IL18. A diverse array of stimuli can activate the NLRP3 inflammasome, including both PAMPs and endogenous host-derived molecules indicative of cellular damage. Because of the divergent qualities of the NLRP3 inflammasome agonists, it has been hypothesized that these agonists converge on a common pathway, with a final endogenous ligand activating NLRP3. NLRP3 agonists share several attributes, including