The NLRP3 inflammasome is a critical platform for the activation of Caspase-1 and secretion of biologically active IL-1? and IL-18 in response to bacterial toxins, particulate matter and certain endogenous stimuli. In addition to its protective role in innate immunity, dysregulation of the inflammasome by missense NLRP3 mutations causes autoinflammatory disorders. Furthermore, aberrant activation of NLRP3 has been linked to the pathogenesis of several acquired inflammatory disorders including gouty arthritis, silicosis, atherosclerosis, diabetes and Alzheimer's disease. In addition to the classical pathway, NLRP3 is activated by the noncanonical inflammasome in response to intracellular lipopolysaccharyde (LPS). Activation of the noncanonical inflammasome leads to Caspase-11-dependent pyroptosis, a proinflammatory form of cell death, which is critical for induction of endotoxic shock in mice. Although much progress has been made about the stimuli and cellular events that activate the NLRP3 inflammasome, a major gap in the field is the identification of molecules that are required for NLRP3 activation and the mechanism of NLRP3 activation. Another major gap is the events downstream of Caspase-11 responsible for pyroptosis in the noncanonical inflammasome pathway and the mechanism by which Caspase-11 activates the NLRP3 inflammasome. We have identified several factors that are required for the activation of NLRP3 and pyroptosis induced by the canonical and noncanonical inflammasomes. In this renewal application, we propose three specific Aims to understand the mechanism of NLRP3 activation and the events downstream of Caspase-11 that regulate pyroptosis and NLRP3 activation. Understanding how NLRP3 is activated and the components of the noncanonical inflammasome pathway required for pyroptosis is expected to provide critical insight into the role of the inflammasomes in host defense against pathogens and bacterial sepsis as well as the development of new therapeutic approaches to prevent and/or treat inflammasome-associated diseases.
NLRP3 is a critical component of the innate immune system that forms the inflammasome, a molecular platform mediating Caspase-1 activation and secretion of biologically active IL-1? and IL-18. In addition to its protective role in innate immunity, dysregulation of the inflammasome by missense NLRP3 mutations causes autoinflammatory disorders and has been implicated in the pathogenesis of several acquired inflammatory disorders including gouty arthritis, silicosis, atherosclerosis, diabetes and Alzheimer's disease. Another important innate immune pathway is that induced by the noncanonical inflammasome. However, the mechanism of NLRP3 activation and the noncanonical inflammasome pathway remain poorly understood. In this grant application, we propose studies to understand the mechanism of NLRP3 activation via the classical and the noncanonical inflammasome.
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