Perturbation of homeostasis, as a result of pathogen invasion or self imbalance, can result in tissue damage and chronic inflammation. In addition to its well-established role in clearance of pathogens or cell corpses, inflammation also promotes tissue repair and regeneration. Conserved from flies to humans, a transient and properly terminated inflammatory response is crucial for restoration of tissue homeostasis after damage and its absence enhances tissue damage, leading to severe immunopathology. A key player in normal and pathological inflammation is the NLRP3 inflammasome, a major sensor of tissue damage, toxic substances and certain pathogens. Aberrant NLRP3 inflammasome activation has been shown to promote the development of gouty arthritis, lupus, atherosclerosis, Alzheimer's disease, macular degeneration and cancer. It is therefore of utmost importance to study the molecular mechanism involved in NLRP3 inflammasome activation during health and disease. NLRP3 inflammasome activation occurs via two distinct steps: ?priming? and ?activation?. Although different events involved in the ?activation? step have been identified, the signaling steps through which NLRP3 inflammasome is activated remains unclear. Even less is understood about ?priming?, which entails synthesis of the caspase-1 substrate pro-IL-1? as well as elevated NLRP3 expression. Recently, I identified interferon regulatory factor 1 (IRF1) as a novel player that is required for NLRP3 inflammasome activation. Of note, LPS- mediated priming results in strong IRF1 induction whereas IRF1 ablation prevents NLRP3 activation without affecting expression of pro-IL-1? or components of the inflammasome. This proposal aims at delineating the entire signaling pathway through which IRF1 controls NLRP3 inflammasome activation, and determining the role of this pathway in the pathogenesis of NLRP3-associated inflammatory disorders. Completion of this study will not only further our knowledge on inflammasome biology, but also provide a new way to interfere with aberrant NLRP3 inflammasome activation in a number of inflammatory diseases.
Aberrant NLRP3 inflammasome activation plays a key role in promoting the development of numerous autoinflammatory, autoimmune, metabolic, degenerative, and aging-related diseases. To better understand the molecular mechanism involved in NLRP3 inflammasome activation during health and disease, this proposal aims at defining the complete signaling pathway by which IRF1, a newly identified player, controls NLRP3 inflammasome activation. Completion of this proposal will not only advance our knowledge in inflammasome biology, but also provide new ways to interfere with pathogenic NLRP3 inflammasome activation.