Secreted Phospholipase A2 Group X Regulation of Type-2 Inflammation

项目总结 2型炎症的部分特征是产生细胞因子IL-5和IL-13，这是一个显著的特征 哮喘的症状。最近，先天免疫系统和获得性免疫系统已被证明在 协调2型炎症在呼吸道中的发展和传播。之前的发现由 我们的团队和其他人已经发现，分泌的PLA2(SPLA2)活性在哮喘患者的呼吸道中增加 哮喘患者，观察到的大部分sPLA2活性归因于一个特定的成员，sPLA2 X组 (sPLA2-X)，主要由上皮细胞和巨噬细胞表达。SPLA2-X的酶活性 有助于呼吸道中的二十烷基类化合物，但sPLA2的功能超出了它们的酶活性 还没有被很好地理解。由于sPLA2-X已被证实参与了人类哮喘的发病环境，我们 寻求更好地确定sPLA2-X在过敏性呼吸道炎症中的作用 实验性哮喘。我们的初步数据表明，1)sPLA2-X的遗传消融可以预防 2型免疫反应的发展和2)作为佐剂给予的sPLA2-X既促进先天和 2型炎症的适应性成分。在本申请中，我们试图揭示 SPLA2-X在呼吸道中启动2型免疫反应。我们的主要假设是sPLA2-X作为 一种通过释放上皮源性细胞因子增强2型免疫反应的佐剂 包括IL-33和ILC2的极化。我们进一步假设TGM2用于增加 SPLA2-X在过敏性炎症发生发展中的作用在目标1中，我们重点关注 用sPLA2-X/OVA模型研究IL-33在推动2型炎症和ILC2极化中的重要性 实验性哮喘。利用小鼠和人的呼吸道上皮细胞，我们研究了 上皮sPLA2-X在促进2型上皮源性细胞因子释放和表达中的作用 发炎。在目标2中，我们研究了TGM2在2型炎症和 TGM2是否通过调节sPLA2-X活性发挥作用。这些研究的完成将提供一个更彻底的 了解sPLA2-X在变态反应性肺部疾病中的功能并进一步验证sPLA2-X是一种新的 哮喘环境中的治疗靶点。

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.