Maturation of IL-1beta and IL-18 in novel macrophage aggresomes

新型巨噬细胞聚集体中 IL-1β 和 IL-18 的成熟

• 批准号: 7642202
• 负责人: Christian Stehlik
• 金额: $ 19.06万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-05 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7642202
• 关键词: Adaptor Signaling Protein; Address; Alzheimer' s Disease; Arthritis; Asthma; Atherosclerosis; Biological; Caspase; Caspase-1; Cell Nucleus; Cellular Stress; Characteristics; Communicable Diseases; Cytosol; Data; Developed Countries; Disease; Dynein ATPase; Family; Fibrosis; Goals; Grant; HDAC6 gene; Human; Image; Immune; Immune response; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Interleukin Activation; Interleukin-1 beta; Interleukin-12; Interleukin-18; Interleukins; Knowledge; Life; Link; Lung; Mediator of activation protein; Medical; Microtubules; Modeling; Molecular; Multiple Sclerosis; Nerve Degeneration; Non-Insulin-Dependent Diabetes Mellitus; Pathogenesis; Pathway interactions; Patients; Pattern recognition receptor; Periodontitis; Phagocytes; Physiological; Positioning Attribute; Process; Production; Proteins; Reaction; Recruitment Activity; Research; Research Proposals; Signal Transduction; Stress; Stroke; Structure; Symptoms; System; Testing; Therapeutic; Time; Time Study; Tissues; Ulcerative Colitis; Work; Wound Healing; base; combat; cytokine; design; effective therapy; high risk; improved; innovation; macrophage; novel; novel strategies; pathogen; prevent; procaspase-1; protein complex; public health relevance; receptor; response; social; therapy development

DESCRIPTION (provided by applicant): Interleukin (IL)-12 and IL-18 are key mediators promoting inflammatory reactions. Localized inflammatory responses are important mechanisms to limit pathogen infections and to promote wound healing. However, excessive and uncontrolled production of IL-12 and IL-18 and resulting inappropriate inflammation is linked to tissue destruction and the debilitating symptoms of the growing number of inflammatory diseases. Processing and release of IL-12 and IL-18 occurs in macrophages in response to formation of inflammasomes. Inflammasomes are activated by cytosolic pattern recognition receptors of the Nod-like receptor (NLR) family in response to pathogen or host derived stress signals. Activated NLRs recruit pro-caspase-1 via the essential adaptor protein ASC (PYCARD), resulting in caspase-1 activation and release of IL-12 and IL-18. The molecular mechanisms that control inflammasome formation and activation are poorly understood, but have a high potential to provide the basis for novel strategies to interfere with IL-12 and IL-18 release for the treatment of inflammatory diseases. Our central hypothesis for the proposed study is that inflammasomes represent inducible, specialized cytosolic structures in macrophages, where inflammasome components are specifically recruited to activate caspase-1. Our hypothesis is based on preliminary imaging results from inflammasomes in macrophages, and in this study we propose to address the mechanism of inducible inflammasome formation and link it to the IL-12 and IL-18 release mechanism. Our hypothesis is based on our preliminary findings showing that (1) inflammasomes require inducible redistribution of inflammasome components; (2) inflammasomes are inducible formed in the cytosol of macrophages; (3) inflammasomes contain characteristic marker proteins that directly link it to specialized cellular ultrastructures. We propose two specific aims: Specific aim #1 will establish inflammasomes as distinct structures in macrophages, while specific aim #2 will determine the impact on IL-12 and IL-18 maturation as a consequence of disrupting formation of these structures. At the completion of this study, we expect to provide the currently elusive mechanism by which inflammasomes assemble in response to infection and stress, which will open new avenues for inhibiting maturation of IL-12 and IL-18. This study will contribute to our long-term goal to contribute to a better understanding of molecular mechanisms of innate immune responses leading to inflammatory pathway activation, in order that improved therapies to treat inflammatory and infectious diseases can be developed. Public Health Relevance: Excessive production of IL-12 and IL-18 are directly responsible for the symptoms of a number of inflammatory diseases with destructive pathogenesis, including some of the most common diseases of industrialized nations, including arthritis, asthma, inflammatory bowel disease, ulcerative colitis, atherosclerosis, periodontitis, type 2 Diabetes, lung fibrosis, multiple sclerosis, Alzheimer's disease, or stroke. Currently there are no effective treatments available, causing patients life-long symptoms and a huge economical and financial impact on our social and medical systems. IL-12 and IL- 18 require specialized protein complexes, referred to as inflammasomes for release, but the mechanism by which inflammasomes assemble are not well understood, but are expected to provide the basis for the development of treatment options for patients suffering from inflammatory diseases. As a consequence, in this study we propose to address the mechanism of inflammasome formation, and to link inflammasomes to existing cellular ultra structures, which is expected to open new avenues for preventing uncontrolled release of IL-12 and IL-18.

描述（由申请人提供）：白细胞介素（IL）-12和IL-18是促进炎症反应的关键介质。局部炎症反应是限制病原体感染和促进伤口愈合的重要机制。然而，IL-12 和 IL-18 的过度和不受控制的产生以及由此产生的不适当的炎症与组织破坏和越来越多的炎症性疾病的衰弱症状有关。 IL-12 和 IL-18 的加工和释放发生在巨噬细胞中，以响应炎症小体的形成。炎症小体由 Nod 样受体 (NLR) 家族的胞质模式识别受体激活，以响应病原体或宿主衍生的应激信号。激活的 NLR 通过必需接头蛋白 ASC (PYCARD) 招募 pro-caspase-1，导致 caspase-1 激活并释放 IL-12 和 IL-18。控制炎症小体形成和激活的分子机制尚不清楚，但很有可能为干扰 IL-12 和 IL-18 释放以治疗炎症性疾病的新策略提供基础。我们对拟议研究的中心假设是，炎症小体代表巨噬细胞中可诱导的、专门的胞质结构，其中炎症小体成分被专门招募来激活 caspase-1。我们的假设基于巨噬细胞炎症小体的初步成像结果，在这项研究中，我们建议解决诱导性炎症小体形成的机制，并将其与 IL-12 和 IL-18 释放机制联系起来。我们的假设基于我们的初步发现，表明（1）炎症小体需要炎症小体成分的诱导性重新分布； (2)巨噬细胞胞质中诱导形成炎症小体； (3) 炎症小体含有特征标记蛋白，可将其与特殊的细胞超微结构直接连接。我们提出了两个具体目标：具体目标#1将建立炎症小体作为巨噬细胞中的独特结构，而具体目标#2将确定由于破坏这些结构的形成而对IL-12和IL-18成熟的影响。这项研究完成后，我们期望提供目前难以捉摸的炎症小体响应感染和应激而组装的机制，这将为抑制 IL-12 和 IL-18 的成熟开辟新途径。这项研究将有助于我们的长期目标，即有助于更好地了解导致炎症途径激活的先天免疫反应的分子机制，以便开发出治疗炎症和传染病的改进疗法。公共卫生相关性：IL-12 和 IL-18 的过量产生直接导致许多具有破坏性发病机制的炎症性疾病的症状，包括工业化国家的一些最常见的疾病，包括关节炎、哮喘、炎症性肠病、溃疡性结肠炎、动脉粥样硬化、牙周炎、2 型糖尿病、肺纤维化、多发性硬化症、阿尔茨海默病或中风。目前尚无有效的治疗方法，导致患者出现终生症状，并对我们的社会和医疗系统造成巨大的经济和财政影响。 IL-12和IL-18需要专门的蛋白质复合物（称为炎症小体）来释放，但炎症小体的组装机制尚不清楚，但有望为炎症性疾病患者的治疗方案开发提供基础。因此，在这项研究中，我们建议解决炎症小体形成的机制，并将炎症小体与现有的细胞超微结构联系起来，这有望为防止 IL-12 和 IL-18 不受控制的释放开辟新途径。