Role of IRF1 in NLRP3 inflammasome activation and inflammatory diseases

摘要 由于病原体入侵或自身不平衡，体内平衡的扰动可导致组织 损伤和慢性炎症。除了其在清除病原体或细胞中的公认作用外， 尸体，炎症也促进组织修复和再生。从苍蝇到人类，一个短暂的 适当终止炎症反应对于损伤后恢复组织稳态至关重要， 它的缺乏增强了组织损伤，导致严重的免疫病理学。一个关键的球员， 病理性炎症是NLRP 3炎性体，其是组织损伤、有毒物质和 某些病原体。异常的NLRP3炎性小体激活已被证明可促进 痛风性关节炎、狼疮、动脉粥样硬化、阿尔茨海默病、黄斑变性和癌症。因此， 因此，研究NLRP3炎性小体在健康过程中活化的分子机制至关重要 和疾病NLRP 3炎性小体活化通过两个不同的步骤发生："引发"和"活化"。虽然 不同的事件参与"激活"的步骤已经确定，通过NLRP 3的信号步骤， 炎性小体是否被激活仍不清楚。对"启动"的理解甚至更少，这需要合成 caspase-1底物pro-IL-1 β以及升高的NLRP 3表达。最近，我发现干扰素 调节因子1（IRF1）作为NLRP 3炎性体激活所需的新参与者。注意，LPS- 介导的引发导致强烈的IRF1诱导，而IRF1消融阻止NLRP 3激活， 影响pro-IL-1 β或炎性小体组分的表达。这项建议旨在界定 IRF1通过其控制NLRP 3炎性小体激活的整个信号通路，并确定其作用 在NLRP3相关炎症性疾病的发病机制中，完成本研究将 这不仅加深了我们对炎性小体生物学的认识，而且为干预异常炎症反应提供了新的途径。 NLRP3炎性小体在许多炎性疾病中的活化。

Abstract 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-1β 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-1β 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.