Role of IRF1 in NLRP3 inflammasome activation and inflammatory diseases

摘要 由于病原体入侵或自身失衡，动态平衡的紊乱可能会导致组织 损伤和慢性炎症。除了在清除病原体或细胞方面具有公认的作用外 身体，炎症也促进组织修复和再生。从苍蝇到人类的遗传，一种过路人 而正确终止炎症反应对于损伤后组织动态平衡的恢复至关重要 它的缺失会加剧组织损伤，导致严重的免疫病理。在Normal And中扮演关键角色 病理性炎症是NLRP3炎症体，是组织损伤、有毒物质和 某些病原体。异常的NLRP3炎性小体激活被证明促进了 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，它是 研究NLRP3炎症小体激活的分子机制在健康中的重要性 和疾病。NLRP3炎症体的激活通过两个不同的步骤进行：“启动”和“激活”。虽然 已经确定了“激活”步骤中涉及的不同事件，NLRP3通过这些信令步骤 炎症小体是否被激活仍不清楚。对“启动”的理解更少，“启动”需要合成 Caspase-1底物前IL-1β和NLRP3表达增加。最近，我发现了干扰素 调节因子1(IRF1)是NLRP3炎症小体激活所必需的一种新的蛋白。值得注意的是，内毒素- 介导的启动导致强烈的IRF1诱导，而IRF1消融则阻止NLRP3的激活 影响原-IL-1β或炎性小体成分的表达。这项建议旨在划定 IRF1调控NLRP3炎症体激活的完整信号通路及其作用 该通路在NLRP3相关炎症性疾病发病机制中的作用。这项研究的完成将 不仅加深了我们对炎症体生物学的认识，而且为干扰异常提供了一种新的方法 NLRP3在一些炎症性疾病中激活炎症体。

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.