Secreted Phospholipase A2 Group X Regulation of Type-2 Inflammation

分泌型磷脂酶 A2 X 组对 2 型炎症的调节

• 批准号: 9325281
• 负责人: James D Nolin
• 金额: $ 5.67万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2020-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9325281
• 关键词: Ablation; Adaptive Immune System; Adjuvant; Allergens; Allergic; Allergic inflammation; Asthma; Automobile Driving; Cell model; Complement; Data; Dependence; Development; Eicosanoids; Environment; Enzymes; Epithelial; Epithelial Cells; Event; Experimental Models; Exposure to; Foundations; Generations; Genetic; Human; Hydrolysis; Immune response; Immune system; Inflammation; Interleukin-13; Interleukin-5; Lead; Leukotrienes; Liquid substance; Lung; Lung Inflammation; Lung diseases; Lymphoid Cell; Lysophospholipids; Mediating; Membrane; Modeling; Mus; Pathogenicity; Patients; Phase; Phospholipase; Phospholipase A2; Phospholipids; Play; Production; Proteins; Pyroglyphidae; Rag1 Mouse; Regulation; Role; Scientist; Source; T-Lymphocyte; TSLP gene; Transgenic Mice; Validation; Work; adaptive immune response; airway epithelium; airway inflammation; allergic airway inflammation; allergic response; asthmatic; asthmatic airway; cytokine; design; in vivo Model; knock-down; macrophage; member; new therapeutic target; polarized cell; receptor; response; small hairpin RNA; transglutaminase 2

Project summary Type-2 inflammation, characterized in part by the production of cytokines IL-5 and IL-13, is a hallmark feature of asthma. Recently, the innate and adaptive immune systems have been shown to play critical roles in coordinating the development and propagation of type-2 inflammation in the airways. Previous discoveries by our group and others have revealed that secreted PLA2 (sPLA2) activity is increased in the airways of asthmatics, with much of the observed sPLA2 activity attributed to one member in particular, sPLA2 group X (sPLA2-X), which is primarily expressed by epithelial cells and macrophages. Enzymatic activity of sPLA2-X contributes to the pool of eicosanoids in the airways, but the function of sPLA2s beyond their enzymatic activity is not well understood. Because of the established involvement of sPLA2-X in settings of human asthma, we seek to better define the function of sPLA2-X during allergic inflammation of the airways using in vivo models of experimental asthma. Our preliminary data suggest that 1) genetic ablation of sPLA2-X protects against the development of a type-2 immune response and 2) sPLA2-X given as an adjuvant promotes both innate and adaptive components of type-2 inflammation. In this application, we seek to uncover the mechanism by which sPLA2-X initiates a type-2 immune response in the airways. Our primary hypothesis is that sPLA2-X acts as an adjuvant to enhance type 2 immune responses through the release of epithelial derived cytokines including IL-33 and polarization of ILC2s. We further postulate that TGM2 serves to augment the function of sPLA2-X during the development of allergic inflammation. In Aim 1, we focus on the importance of IL-33 in driving type-2 inflammation and ILC2 polarization using a sPLA2-X/OVA model of experimental asthma. Using murine and human airway epithelial cells, we examine the specific contribution of epithelial sPLA2-X function in the release and expression of epithelial-derived cytokines that promote type-2 inflammation. In Aim 2 we examine the involvement of TGM2 in the development of type-2 inflammation and whether TGM2 acts by regulating sPLA2-X activity. Completion of these studies will provide a more thorough understanding of sPLA2-X function in allergic lung disease and further validation of sPLA2-X as a novel therapeutic target in settings of asthma.

项目摘要 以产生细胞因子IL-5和IL-13为部分特征的2型炎症是一个标志性特征 哮喘最近，先天性和适应性免疫系统已被证明在免疫系统中发挥关键作用。 协调气道中2型炎症的发展和传播。先前的发现 我们的研究小组和其他人已经揭示，分泌型PLA 2（sPLA 2）活性在哮喘患者的气道中增加， 哮喘患者，观察到的sPLA 2活性大部分归因于一个成员，特别是sPLA 2 X组 （sPLA 2-X），其主要由上皮细胞和巨噬细胞表达。sPLA 2-X的酶活性 有助于气道中的类花生酸池，但sPLA 2的功能超出其酶活性 并没有得到很好的理解。由于sPLA 2-X参与了人类哮喘的发生，我们 目的是使用气道过敏性炎症的体内模型，更好地确定sPLA 2-X在气道过敏性炎症中的功能， 实验性哮喘我们的初步数据表明：1）基因切除sPLA 2-X可以防止 2型免疫应答的发展和2）作为佐剂给予的sPLA 2-X促进先天性和 2型炎症的适应性成分。在这个应用中，我们试图揭示的机制， sPLA 2-X在气道中启动2型免疫应答。我们的主要假设是sPLA 2-X作为 一种通过释放上皮衍生的细胞因子来增强2型免疫应答的佐剂 包括IL-33和ILC 2的极化。我们进一步假设，TGM 2有助于增加 sPLA 2-X在变应性炎症发展过程中的作用在目标1中，我们关注 使用sPLA 2-X/OVA模型研究IL-33在驱动2型炎症和ILC 2极化中的重要性 实验性哮喘使用小鼠和人气道上皮细胞，我们研究了 上皮sPLA 2-X在上皮源性细胞因子的释放和表达中的功能， 炎症在目的2中，我们研究了TGM 2在2型炎症发展中的参与， TGM 2是否通过调节sPLA 2-X活性发挥作用。这些研究的完成将提供一个更全面的 了解sPLA 2-X在变应性肺病中的功能，并进一步验证sPLA 2-X作为一种新的 哮喘治疗的目标。