Macrophage inflammasome regulation

巨噬细胞炎症小体调节

• 批准号: 8193948
• 负责人: Mark Damian Wewers
• 金额: $ 38.13万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-15 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8193948
• 关键词: Actin-Binding Protein; Actins; Acute Lung Injury; Adaptor Signaling Protein; Address; Adult Respiratory Distress Syndrome; Affect; Asthma; Caspase; Caspase-1; Cell membrane; Cell surface; Cells; Cleaved cell; Complex; Cytoskeleton; Cytosol; Data; Dimerization; Disease; Encapsulated; Enzymes; Epithelium; Exocytosis; Fibroblasts; Fibrosis; Hormones; IL8 gene; Immune; Inflammation; Inflammatory; Interleukin-1; Interleukin-18; Link; Lung; Lung Inflammation; Lung diseases; Microfilaments; Modeling; Mononuclear; Natural Immunity; Oranges; Phagocytes; Pneumonia; Process; Proteins; Pulmonary Fibrosis; Receptor Cell; Regulation; Role; Rupture; Sepsis; Signal Transduction; Structure; Structure of parenchyma of lung; Surface; Testing; Thymosin; Vesicle; Work; cytokine; macrophage; marenostrin; novel; pathogen; receptor; response; sensor

DESCRIPTION (provided by applicant): Innate immunity's importance in lung defense against external challenges has been heightened by the recent discovery of distinct intracellular pathogen recognition receptors that detect danger signals that gain access to the cytosol of macrophages. These receptors include NOD-like receptors (NLRs) as well as NOD independent sensors such as pyrin. A critical function of the intracellular sensors is to regulate the enzyme caspase-1 through an inflammasome complex. In an inflammasome, NLRs and NOD-independent sensors interact, via pyrin domains (PYD) or caspase recruitment domains (CARD), with an adaptor protein, ASC, to induce caspase-1 dimerization and autoactivation. Caspase-1 then cleaves and activates the precursors of IL-1¿ and IL-18, molecules that have been strongly associated with asthma, ARDS, pneumonia and pulmonary fibrosis. However, despite this conceptual advance, it remains obscure how this inflammasome complex is physically linked to IL-1¿ processing and release, limiting our understanding of lung inflammation and our ability to create new therapies. In this context, the present application seeks to expand upon the inflammasome hypothesis by linking its structure and function to the mechanisms that promote the release of the leaderless protein IL-1¿. We propose a novel structure, the releasosome. We hypothesize that this novel exosomal structure encapsulates proIL-1¿ together with inflammasome components in an actin filament regulated vesicle. Pyrin and ASC are known actin binding proteins. Thus, in this model, microvesicular IL-1¿ is presented to target cell membranes (e.g. lung fibroblasts or epithelium) in a highly concentrated packet where its secondary exocytosis can be controlled by target cell receptors that modulate local concentrations of ATP (a classical inflammasome activating factor). The project proposes to test the following specific hypotheses, 1) IL-1¿ release is predominantly from exosomes; 2) the target cell induced rupture of these exosomes provides a mechanism to focus IL-1¿ activity; 3) pyrin and ASC interactions modulate the exosomal packaging of caspase-1 for release; and 4) actin interactions with proIL-1¿ are critical to exosomal inflammasome proIL-1¿ interaction. If confirmed, these novel hypotheses will change our concepts about IL-1¿ regulation and provide new treatment options for inflammatory lung disorders. PUBLIC HEALTH RELEVANCE: Most inflammatory disorders of the lung (e.g. sepsis, acute lung injury, asthma, lung fibrosis and pneumonia) are affected by IL-1¿, a hormone (or cytokine) that is produced by lung macrophages and central to inducing inflammation. We have new data to show that the release of IL-1¿ by macrophages occurs in discreet tiny packets called microvesicles. The work proposed will test how packaging of IL-1¿ into these vesicles occurs and how this packaging affects IL-1¿ responses in lung tissue. Results of this work will greatly impact our understanding of innate immune mechanisms and provide novel chances to treat lung inflammatory disorders.

描述（由申请人提供）：最近发现了独特的细胞内病原体识别受体，这些受体可以检测进入巨噬细胞胞浆的危险信号，从而证明了先天免疫在肺部防御外部挑战中的重要性。这些受体包括 NOD 样受体。 NLRs）以及 NOD 独立传感器，例如pyrin，细胞内传感器的一个关键功能是通过炎症小体复合物调节 caspase-1。 NLR 和不依赖 NOD 的传感器通过热蛋白结构域 (PYD) 或半胱天冬酶募集结构域 (CARD) 与接头蛋白 ASC 相互作用，诱导 caspase-1 二聚化和自动激活，然后裂解并激活 IL-1 的前体。 1??和IL-18，这些分子与哮喘、ARDS、肺炎和肺纤维化密切相关。然而，尽管在概念上取得了进展，但这种炎性复合物与IL-1的物理联系仍然不清楚。处理和释放，限制了我们对肺部炎症的理解以及我们创造新疗法的能力在这种情况下，本申请试图通过将其结构和功能与促进无前导蛋白IL的释放的机制联系起来来扩展炎症小体假设。 -1¿我们提出了一种新颖的结构，即释放体，我们认为这种新颖的外泌体结构封装了 proIL-1¿与肌动蛋白丝调节囊泡中的炎症小体成分一起，Pyrin 和 ASC 是已知的肌动蛋白结合蛋白，因此，在该模型中，微泡 IL-1¿以高度浓缩的形式呈现给靶细胞膜（例如肺成纤维细胞或上皮细胞），其中其二次胞吐作用可以通过调节 ATP（一种经典炎症体激活因子）局部浓度的靶细胞受体来控制。该项目建议测试以下内容。具体假设，1) IL-1¿释放主要来自外泌体；2) 靶细胞诱导的这些外泌体破裂提供了聚焦 IL-1 的机制活性；3) 吡啶和 ASC 相互作用调节 caspase-1 的外泌体包装的释放；4) 肌动蛋白与 proIL-1 的相互作用对于外泌体炎性体 proIL-1 至关重要？如果得到证实，这些新颖的假设将改变我们对 IL-1 的概念。调节并为炎症性肺部疾病提供新的治疗选择。 公共卫生相关性：大多数肺部炎症性疾病（例如脓毒症、急性肺损伤、哮喘、肺纤维化和肺炎）均受 IL-1 影响，一种由肺巨噬细胞产生的激素（或细胞因子），对于诱导炎症至关重要。我们有新的数据表明 IL-1 的释放。巨噬细胞产生的微小包被称为微泡，这项工作将测试 IL-1 的包装方式。进入这些囊泡中发生以及这种包装如何影响 IL-1¿这项工作的结果将极大地影响我们对先天免疫机制的理解，并为治疗肺部炎症性疾病提供新的机会。