P2X7 and the Inflammasome Pathways in Lung Inflammation

大量的研究表明，环境刺激影响哮喘的发病机制， 触发急性事件，并通过塑造发展适应性免疫反应的特点， 疾病我们对哮喘肺对先天性刺激的免疫反应的研究， 内毒素的研究主要集中在Toll受体的作用上，Toll受体是细胞表面分子， 识别警告细胞响应外来代理的存在。一些实验室最近的研究， 包括我们的合作者丁博士，已经确定了一个新的基因家族，最初被称为 CATERPILLER基因，在细胞对环境损伤的反应中起关键作用。这些 基因编码以pyrin、核结合和富含亮氨酸结构域为特征的细胞质蛋白，类似于 与Toll受体中发现的蛋白质相似在对各种刺激的反应中，已经显示了许多这些蛋白质 组装成称为"炎性小体"的复合物， 环境威胁。在与CATERPILLER基因中的三个形成复合物的情况下，Nlrpl， cryopyrin/Mrp3和Nlrc4/lpaf1，这种反应包括细胞因子的产生和细胞因子的启动。 导致坏死或凋亡的事件。我们小组以前的研究表明，ATP是必需的， IL-1 β的成熟和从内毒素致敏的小鼠巨噬细胞中的释放，而且， 由ATP激活的离子通道P2X7介导。已经出现了一种模型，其中P2X7的激活 导致细胞内K+的改变，这反过来又导致一些炎性小体的活化。更 最近，有人提出P2X7募集半通道泛连接蛋白-1，这种复合物 介导细菌分子从内体区室到宿主胞质溶胶的通道， 炎性小体激活。本申请的总体假设是， P2X7/炎性小体通路在细胞对环境刺激的反应中起重要作用， 调节IL-1细胞因子家族的成熟和释放以及调节细胞凋亡 肺对这些刺激的反应。因此，这一途径既可以促进糖尿病的发病， 哮喘以及由环境刺激引发的疾病恶化。

A large number of studies indicate that environmental stimuli impact the pathogenesis of asthma both by triggering acute events and by molding the developing adaptive immune responses characteristic of this disease. Much of our study of the immune response of the asthmatic lung to innate stimuli such as endotoxin has focused on the role of the Toll receptors, cell surface molecules which through pattern recognition alert the cell in response to the presence of foreign agents. Recent studies by a number of labs, including that of our collaborator Dr. Ting, have identified a novel family of genes, initially termed CATERPILLER genes, which play a critical role in the response of cells to environmental insults. These genes encode cytoplasmic proteins characterized by pyrin, nuclear binding, and leucine-rich domains, similar to those found in Toll receptors. In response to various stimuli, a number of these proteins have been shown to assemble into complexes termed "inflammasomes" which help to orchestrate the response of the cell to the environmental threat. In the case of complexes formed with three of the CATERPILLER genes, Nlrpl, cryopyrin/Mrp3, and Nlrc4/lpaf1, this response includes the production of cytokines and the initiation of events that lead to necrosis or apoptosis. Previous studies by our group have shown that ATP is required for the maturation and release of IL-1(3 from endotoxin primed mouse macrophages and, furthermore, that this is mediated by ATP activation of the ion channel, P2X7. A model has emerged in which activation of P2X7 leads to alteration in intracellular K+, which in turn leads to activation of some inflammasomes. More recently, it has been suggested that P2X7 recruits the hemichannel pannexin-1 and that this complex mediates the passage of bacterial molecules from the endosomal compartment to the host cytosol leading to inflammasome activation. The overall hypothesis of this application is that the activation of the P2X7/inflammosome pathway plays an important part in the response of cells to environmental stimuli, regulating both the maturation and release of the family of IL-1 cytokines and modulating the apoptotic response of the lung to these stimuli. This pathway, therefore, can contribute both to the pathogenesis of asthma as well as to disease exacerbations triggered by environmental stimuli.