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）：白介素（IL）-12和IL-18是促进炎症反应的关键介体。局部炎症反应是限制病原体感染并促进伤口愈合的重要机制。但是，IL-12和IL-18的过度和不受控制的产生以及导致的不当炎症与组织破坏以及日益增长的炎症性疾病症状有关。 IL-12和IL-18的加工和释放是在巨噬细胞中发生的，响应炎症的形成。炎症体是通过响应病原体或宿主衍生的应激信号的NOD样受体（NLR）家族的胞质模式识别受体激活的。激活的NLRS通过必需的衔接蛋白ASC（Pycard）募集了pro-Caspase-1，从而导致caspase-1激活和IL-12和IL-18的释放。控制炎性体形成和激活的分子机制知之甚少，但具有很高的潜力，可以为干扰IL-12和IL-18释放以治疗炎症性疾病的新型策略提供基础。我们对拟议研究的中心假设是，炎症体代表了巨噬细胞中诱导的，专门的胞质结构，在该巨噬细胞中，炎性组成分专门募集以激活caspase-1。我们的假设基于巨噬细胞中炎症的初步成像，在本研究中，我们建议解决诱导型炎性体形成的机制，并将其与IL-12和IL-18释放机制联系起来。我们的假设是基于我们的初步发现，表明（1）炎症需要诱导的炎性组成分的诱导重新分布； （2）在巨噬细胞的细胞质中形成炎症； （3）炎性症包含特征性标记蛋白，将其直接连接到专门的细胞超微结构。我们提出了两个具体目标：特定目标＃1将建立炎症，作为巨噬细胞中不同的结构，而特定的目标＃2将决定对IL-12和IL-18的影响，因为破坏了这些结构的形成。这项研究完成后，我们希望提供当前难以捉摸的机制，通过这些机制，炎症响应感染和压力的响应，这将为抑制IL-12和IL-18的成熟而开放新的途径。这项研究将有助于我们的长期目标有助于更好地理解导致炎症途径激活的先天免疫反应的分子机制，以便可以发展为治疗炎症和感染性疾病的疗法。 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疾病或中风。目前尚无有效的治疗方法，会导致患者终身症状以及对我们的社会和医疗系统的巨大经济和财务影响。 IL-12和IL-18需要专门的蛋白质复合物，称为炎症症状，但炎性症组合组装的机制尚不清楚，但有望为患有炎症性疾病患者的治疗选择提供基础。结果，在这项研究中，我们建议解决炎性体形成的机制，并将炎性症与现有的细胞超结构联系起来，这有望开放新的途径，以防止不受控制的IL-12和IL-18的释放。