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）：最近发现了不同的细胞内病原体识别受体，这些受体检测进入巨噬细胞胞质溶胶的危险信号，从而提高了先天免疫在肺防御外部挑战中的重要性。这些受体包括NOD样受体（NLR）以及NOD非依赖性传感器，如pyrin。细胞内传感器的一个关键功能是通过炎性体复合物调节酶半胱天冬酶-1。在炎性小体中，NLR和NOD非依赖性传感器通过pyrin结构域（PYD）或半胱天冬酶募集结构域（CARD）与衔接蛋白ASC相互作用，以诱导半胱天冬酶-1二聚化和自激活。半胱天冬酶-1然后切割并激活IL-1和IL-18的前体，这些分子与哮喘、ARDS、肺炎和肺纤维化密切相关。然而，尽管有这一概念上的进步，但这种炎性体复合物如何与IL-1的加工和释放发生物理联系仍然不清楚，这限制了我们对肺部炎症的理解和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-1的释放的机制联系起来来扩展炎性小体假说。我们提出了一种新的结构，释放体。我们假设这种新的外泌体结构将proIL-1？与炎性体成分一起封装在肌动蛋白丝调节的囊泡中。Pyrin和ASC是已知的肌动蛋白结合蛋白。因此，在该模型中，微囊泡IL-1以高度浓缩的包形式呈递给靶细胞膜（例如肺成纤维细胞或上皮细胞），其中其次级胞吐作用可由调节ATP（经典炎性体活化因子）局部浓度的靶细胞受体控制。该项目提出测试以下特定假设：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？活性的机制; 3）pyrin和ASC相互作用调节caspase-1的外泌体包装以释放; 4）肌动蛋白与proIL-1？的相互作用对外泌体炎性体proIL-1？相互作用至关重要。如果得到证实，这些新的假设将改变我们关于IL-1调节的概念，并为炎症性肺部疾病提供新的治疗选择。 公共卫生相关性：肺的大多数炎性病症（例如败血症、急性肺损伤、哮喘、肺纤维化和肺炎）受到IL-1的影响，IL-1是一种由肺巨噬细胞产生的激素（或细胞因子），并且是诱导炎症的中心。我们有新的数据表明，巨噬细胞释放IL-1发生在被称为微泡的离散的小包中。这项工作将测试IL-1是如何包装到这些囊泡中的，以及这种包装如何影响肺组织中的IL-1反应。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。