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: 10341160
• 负责人: Andrea Dorfleutner
• 金额: $ 64.14万
• 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 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10341160
• 关键词: Address; Affect; Alzheimer' s Disease; Asbestosis; Asthma; Atherosclerosis; Autoantibodies; Binding; Biochemical; Biochemical Genetics; 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; Immune; Impairment; Individual; Infectious Agent; Inflammasome; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Innate Immune Response; Interleukin-1 beta; Interleukin-18; Knockout Mice; Link; Malignant Neoplasms; Mediating; Medical; 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; base; conditional knockout; cytokine; cytokine therapy; design; disabling symptom; disorder control; genetic approach; human disease; improved; innate immune pathways; kidney dysfunction; macrophage; marenostrin; mutant; novel; novel therapeutics; particle; pathogen; pathogenic microbe; 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 嗜热性细胞死亡。此外，炎症小体释放聚合的ASC危险颗粒(PASC)，这是 维持和传播炎症体对旁观者细胞和PASC以及PASC自身的反应 在炎症性疾病患者血清中发现抗体。此外，细胞因子的释放由非规范的 炎症体也需要典型的NLRP3炎症体。然而，通过这些机制 炎性小体得到控制在很大程度上是难以捉摸的。过量和失控的NLRP3和吡啶 炎症体活动导致自身炎症性疾病、冰冻病变和家族性地中海 分别是发烧。鉴于IL-1、β和IL-18在宿主防御中的重要作用，以及IL-18的致病机制 炎症性疾病，阐明炎症性小体激活的机制有望有重大意义 对医疗领域的影响，将是设计新的和改进的治疗方案的关键 炎症性疾病患者。 利用蛋白质组学的方法，我们发现了一种新的炎症体成分，并确定了它的作用 在介导炎性小体激活的新的和必要的步骤中，通过促进不同的泛素化 炎症体成分，使人联想到其他关键的先天免疫途径。此外，我们发现， 这种蛋白是炎症小体激活时释放的PASC危险颗粒的一部分。这项研究 本提案中概述的是为了定义这一新的激活步骤的潜在分子机制(S 在人类巨噬细胞和我们新产生的条件性基因敲除小鼠中，它们在 炎性小体激活及其通过PASC危险对炎性小体反应传播的影响 粒子。我们将结合生化和遗传方法进行全面分析，重点是 人类疾病中的关键炎症体，即NLRP3和PYRIN及其引起的疾病 不受控制的炎性小体，以及剖析这种激活和在人类中的传播机制 隐尿管病患者。 我们希望我们的研究将发现改变我们目前生活方式的新的分子机制 了解炎症性疾病的病理机制及其在健康人群中的控制机制 防止不适当的炎症小体激活的个体。因此，我们的研究将具有非常重要的意义 对于更好地理解疾病的病理机制和为开发新的 治疗使患者受益，因此将对人类健康产生积极影响。