Role of IRF1 in NLRP3 inflammasome activation and inflammatory diseases

IRF1在NLRP3炎症小体激活和炎症疾病中的作用

• 批准号: 9599233
• 负责人: Zhenyu Zhong
• 金额: $ 16.2万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-24 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9599233
• 关键词: Ablation; Accounting; Adaptor Signaling Protein; Affect; Aging; Alzheimer' s Disease; Atherosclerosis; Autoimmune Process; Biology; CASP1 gene; Cells; Chronic; Degenerative Disorder; Development; Disease; Event; Family; Gout; Gouty Arthritis; Health; Hepatitis; Homeostasis; Human; IRF1 gene; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1 beta; Interleukin-18; Knowledge; Lead; Lupus; Macular degeneration; Malignant Neoplasms; Mediating; Metabolic; Metabolic Diseases; Metabolic dysfunction; Mitochondria; Mitochondrial DNA; Molecular; Natural regeneration; Non-Insulin-Dependent Diabetes Mellitus; Nucleic Acids; Oxides; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Pattern; Pattern recognition receptor; Periodicity; Phosphotransferases; Play; Poison; Process; Role; Sepsis; Signal Pathway; Signal Transduction; Stimulus; Syndrome; Testing; Tissues; autoinflammatory; base; body sense; cytokine; fly; immunopathology; in vivo; macrophage; novel; pathogen; pathogenic microbe; prevent; protein complex; receptor; recruit; repaired; response; restoration; sensor; tissue regeneration; tissue repair; virtual

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.

抽象的 由于病原体入侵或自我失衡，稳态的扰动可能导致组织 损害和慢性炎症。除了其在清除病原体或细胞清除中的良好作用外 尸体，炎症还促进组织修复和再生。从苍蝇到人类保守，瞬态 适当终止的炎症反应对于损害后的组织稳态恢复至关重要 它的缺失会增强组织损伤，导致严重的免疫病理学。正常的关键人物 病理炎症是NLRP3炎性体，这是组织损伤，有毒物质和 某些病原体。异常的NLRP3炎性体激活已被证明可以促进 盖蒂关节炎，狼疮，动脉粥样硬化，阿尔茨海默氏病，黄斑变性和癌症。因此是 研究健康期间NLRP3炎症体激活的分子机制的最重要性 和疾病。 NLRP3炎性体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，这是NLRP3的信号传导步骤 激活的炎症体尚不清楚。关于“启动”的理解更少，这需要合成 caspase-1底物pro-IL-1β以及NLRP3表达升高。最近，我确定了干扰素 调节因子1（IRF1）是NLRP3炎性体激活所需的新型玩家。值得注意的是，lps- 介导的启动会导致强大的IRF1诱导，而IRF1消融可防止NLRP3激活没有 影响Pro-IL-1β的表达或炎性体的成分。该建议旨在描述 IRF1控制NLRP3炎症体激活并确定角色的整个信号通路 NLRP3相关炎症性疾病的发病机理中这种途径的。这项研究的完成将 我们不仅进一步了解炎性生物学的知识，而且还提供了一种新的干预方式 许多炎症性疾病中的NLRP3炎性体激活。