P2X7 and the Inflammasome Pathways in Lung Inflammation

大量研究表明，环境刺激通过以下途径影响哮喘的发病机制 触发急性事件，并通过塑造发育中的适应性免疫反应 疾病。我们对哮喘肺对先天刺激的免疫反应的大部分研究 内毒素一直专注于Toll受体的作用，Toll受体是细胞表面的分子，通过模式 识别对细胞发出警报，以响应外来特工的存在。多个实验室最近进行的研究， 包括我们的合作者丁博士，已经发现了一个新的基因家族，最初被称为 毛虫基因，在细胞对环境侮辱的反应中发挥关键作用。这些 基因编码胞质蛋白，其特征是吡喃、核结合和富含亮氨酸的结构域，类似 与在Toll受体中发现的那些相同。作为对各种刺激的反应，已经显示了许多这样的蛋白质 组装成称为“炎性小体”的复合体，帮助协调细胞对 环境威胁。在与三个卡特彼勒基因、Nlrp1、 这个反应包括细胞因子的产生和细胞因子的启动。 导致坏死或细胞凋亡的事件。我们小组之前的研究表明，ATP是 内毒素刺激的小鼠巨噬细胞IL-1(3)的成熟和释放，而且，这是 由离子通道P2X7的ATP激活所介导。已经出现了一种模型，在这种模型中，P2X7的激活 导致细胞内K+的变化，进而导致一些炎症体的激活。更多 最近，有研究表明，P2X7招募了半通道pannin-1，并且这个复合体 介导细菌分子从内体隔室到宿主胞浆的通道，从而导致 炎性小体激活。这个应用程序的总体假设是激活 P2X7/炎症体通路在细胞对环境刺激的反应中起着重要作用。 调节IL-1细胞因子家族成熟和释放及调节细胞凋亡 肺对这些刺激的反应。因此，这一途径可以在两种疾病的发病机制中发挥作用。 与哮喘以及由环境刺激引发的疾病恶化有关。

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.