A novel essential inflammasome component propagating inflammatory responses

传播炎症反应的新型重要炎症体成分

• 批准号: 10577887
• 负责人: Andrea Dorfleutner
• 金额: $ 62.6万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-04 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10577887
• 关键词: Address; Affect; Alzheimer' s Disease; Asbestosis; Asthma; Atherosclerosis; Autoantibodies; Binding; Biochemical; Biological; CASP1 gene; Cell Death; Cells; Clinical; Complex; Data; Defect; Diabetes Mellitus; Disease; Familial Mediterranean Fever; Generations; Genetic Models; Goals; Gouty Arthritis; Health; Homeostasis; Host Defense; Human; IL18 gene; Immune; Impairment; Individual; Infectious Agent; Inflammasome; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Innate Immune Response; Interleukin-1 beta; Knockout Mice; Link; Macrophage; Malignant Neoplasms; Mediating; Medical; Microbe; Molecular; Multiple Sclerosis; Mus; Myelogenous; Pathology; Patients; Pattern; Polymers; Positioning Attribute; Property; Proteins; Proteomics; Psoriasis; Regulation; Research; Rheumatoid Arthritis; Role; Sensory; Silicosis; Sterility; Tissues; Ubiquitination; autoinflammatory diseases; conditional knockout; cytokine; cytokine therapy; design; disabling symptom; genetic approach; human disease; improved; innate immune pathways; kidney dysfunction; marenostrin; mutant; novel; novel therapeutics; particle; pathogen; prevent; response; tool; ubiquitin-protein ligase; uptake; wound healing

Inflammasomes are key for the release of the inflammatory cytokines IL-1β, IL-18 and the induction of pyroptotic cell death. In addition, inflammasomes release polymerized ASC danger particles (pASC), which perpetuate and propagate inflammasome responses to bystander cells and pASC as well as pASC auto- antibodies are found in inflammatory disease patient sera. In addition, cytokine release by the non-canonical inflammasome also requires the canonical NLRP3 inflammasome. However, the mechanisms by which inflammasomes are controlled are largely elusive. Excessive and uncontrolled NLRP3 and Pyrin inflammasome activity causes the autoinflammatory diseases Cryopyrinopathies and familial Mediterranean fever, respectively. Given the important roles of IL-1β and IL-18 in host defense and the pathology of inflammatory diseases, elucidating the mechanism of inflammasome activation is expected to have a major impact on the medical field and will be crucial for designing novel and improved treatment options for inflammatory disease patients. Using a proteomics approach, we discovered a novel inflammasome component and identified its role in mediating a novel and essential step of inflammasome activation, by promoting a distinct ubiquitination of inflammasome components, reminiscent to other key innate immune pathways. Furthermore, we discovered that this protein is part of the pASC danger particle released upon inflammasome activation. The research outlined in this proposal is geared to define the underlying molecular mechanism(s) of this novel activation step in human macrophages and our novel generated conditional knock-out mice, which are defect in inflammasome activation and the impact on inflammasome response propagation through pASC danger particles. We will perform a comprehensive analysis combining biochemical and genetic approaches focusing on key inflammasomes involved in human disease, namely NLRP3 and Pyrin and the diseases caused by their uncontrolled inflammasomes, as well as dissecting this activation and propagation mechanism in human Crypyrinopathy patients. We expect that our research will uncover novel molecular mechanisms that change our current understanding of the pathologies of inflammatory disease and the control mechanisms present in healthy individuals to prevent inappropriate inflammasome activation. Our studies will therefore be highly significant and relevant for better understanding disease pathologies and for providing the basis for developing novel therapies to benefit patients and will therefore positively affect human health.

炎性小体是释放炎性细胞因子IL-1β、IL-18和诱导炎症反应的关键。 自燃性细胞死亡此外，炎性小体释放聚合的ASC危险颗粒（pASC）， 使对旁观者细胞和pASC以及pASC自身的炎性体应答永久化并传播， 抗体存在于炎性疾病患者血清中。此外，非典型细胞因子释放 炎性小体也需要典型的NLRP 3炎性小体。然而， 控制炎性小体的方法在很大程度上是难以捉摸的。过量和不受控制的NLRP 3和Pyrin 炎性体活性导致自身炎性疾病Cryopyrinopathies和家族性地中海 发烧，分别。鉴于IL-1β和IL-18在宿主防御和肿瘤病理学中的重要作用， 炎症性疾病，阐明炎性小体激活的机制，预计将有一个重大的 对医疗领域的影响，并将是至关重要的设计新的和改进的治疗方案， 炎症性疾病患者。 利用蛋白质组学方法，我们发现了一种新的炎性体成分，并确定了其作用 在介导炎性小体激活的一个新的和必要的步骤中，通过促进 炎性体成分，让人联想到其他关键的先天免疫途径。此外，我们发现， 这种蛋白质是炎性小体激活后释放的pASC危险颗粒的一部分。研究 在这个建议中概述的是适合于定义这个新的活化步骤的潜在分子机制 在人类巨噬细胞和我们新产生的条件性基因敲除小鼠中， 炎性小体激活和通过pASC危险对炎性小体反应传播的影响 粒子我们将结合生物化学和遗传学方法进行全面分析， 涉及人类疾病的关键炎性小体，即NLRP 3和Pyrin及其引起的疾病 不受控制的炎性小体，以及解剖这种激活和传播机制，在人类 隐睾症患者。 我们希望我们的研究将揭示新的分子机制，改变我们目前的 了解炎症性疾病的病理学和健康人中存在的控制机制， 个体以防止不适当的炎性小体激活。因此，我们的研究将非常重要 并与更好地理解疾病病理学和为开发新的 这些疗法将使患者受益，因此将对人类健康产生积极影响。