The NLRP3 inflammasome has been linked to both protective and pathologic immune responses. Its appropriate activation triggers the innate immune response to invading pathogens including influenza virus, Staphylococcus aureus and Candida albicans; in contrast the NLRP3 inflammasome has been implicated in mediating the pathology associated with a variety of sterile inflammatory diseases. Activation of the NLRP3 inflammasome is a multistep process that culminates in the activation of the cysteine protease caspase-1, which subsequently results in the processing and secretion of the proinflammatory cytokines IL-1 and IL-18. The precise steps leading to activation of the NLRP3 inflammasome are not well understood but have been shown to involve mitochondrial dysfunction and cation flux. We have further identified a novel required step in this pathway and show that the mitochondrial specific lipid cardiolipin directly binds to NLRP3 and activates the NLRP3 inflammasome. In this proposal we specifically dissect the mechanism by which cardiolipin, found on the inner mitochondrial membrane, can interact with cytosolic NLRP3 using in vitro and in vivo approaches. We will determine the mechanism by which calcium flux and the generation of reactive oxygen species trigger the critical interaction between NLRP3 and the mitochondrion. Activation of the NLRP3 inflammasome also requires oligomerization and assembly of the inflammasome components but the triggers for this and timing of these steps are not understood. We will assess the requirement of mitochondrial cardiolipin, calcium flux, and reactive oxygen species in these conserved steps leading to NLRP3 inflammasome activation. Numerous sterile inflammatory processes have been shown to be dependent upon activation of the NLRP3 inflammasome. We have previously shown the inflammatory response to acetaminophen-induced hepatotoxicity is dependent upon the activation of the NLRP3 inflammasome and that mice deficient in components of the NLRP3 inflammasome are protected from acute liver failure. We will use acetaminophen- induced hepatotoxicity as a model of NLRP3-dependent pathogenic sterile inflammation to apply our novel knowledge of the mechanism of activation of the NLRP3 inflammasome. Our findings will allow us to identify new avenues of intervention to modulate the NLRP3-dependent pathologic inflammatory response associated with acetaminophen toxicity and thereby abort the progression of hepatic injury to irreversible liver failure.
Activation of the NLRP3 inflammasome is a critical event in the progression of a number of sterile inflammatory diseases. Our ability to target this sterile inflammatory response is limited by a lack of understanding of how the NLRP3 inflammasome is activated. We propose to identify these unknown steps required for NLRP3 inflammasome assembly and activation and thereby reveal new therapeutics avenues to cut off the progression of tissue damage in sterile inflammatory diseases.
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