Regulation of airway epithelial cell-mediated inflammation by CRAC channels

摘要 Ca~(2+)是一种无处不在的信号信使，调节许多基本功能，如 兴奋性、胞吐和转录。在呼吸道上皮细胞(AECs)中 钙信号传导肺的呼吸道，与多种细胞功能有关 通过影响酶的级联反应和转录因子。钙离子动态平衡也是 与包括活性氧(ROS)在内的其他信号系统紧密结合， 它本身具有许多细胞功能，并与过敏性肺部疾病和 受伤。我们最近发现，储存操作的钙释放激活的钙(CRAC) 通道是支气管上皮细胞钙离子内流的主要途径 激活会导致多种促炎细胞因子水平的增加。然而， 血管内皮细胞CRAC通道在介导气道炎症中的广泛意义及其潜在意义 与ROS和其他介导炎症的信号通路的串扰仍不清楚。我们 假设CRAC通道是控制产生 血管内皮细胞炎症介质对细胞表面G蛋白偶联刺激的反应 受体，如蛋白酶激活的和ATP受体，是一种重要的介导物 哮喘等疾病中的肺部炎症。我们将通过以下方式解决这一假设 三个具体目标：1)检查CRAC通道对过敏原的生理贡献- 介导的ATP释放和确定这种释放如何刺激炎性细胞因子 从AEC，2)研究CRAC通道和 线粒体ROS信号和评估这种串扰对炎性细胞因子的影响 生成，以及3)评估CRAC通道对调节呼吸道的贡献 室内粉尘螨致哮喘小鼠体内炎症反应。加在一起，这些 研究将促进我们对CRAC通道如何调节细胞钙依赖的理解 调节过敏原刺激的呼吸道炎症介质的信号通路，以及 推进开发过敏性呼吸道疾病新疗法的探索。

Abstract Ca2+ is a ubiquitous signaling messenger mediating many essential functions such as excitability, exocytosis and transcription. In the airway epithelial cells (AECs) lining the conducting airways of the lung, Ca2+ signals are implicated in numerous cellular functions through effects on enzymatic cascades and transcriptional factors. Ca2+ homeostasis is also closely integrated with other signaling systems including that of reactive oxygen species (ROS), which has many cellular functions of its own and is implicated in allergic lung diseases and injury. We have recently shown that store-operated Ca2+ release-activated Ca2+ (CRAC) channels serve as the main pathway for Ca2+ entry in bronchial epithelial cells and their activation leads to increases in levels of numerous proinflammatory cytokines. However, the broader significance of CRAC channels in AECs for mediating airway inflammation and potential crosstalk with ROS and other signaling pathways mediating inflammation remains unknown. We hypothesize that CRAC channels are a major mechanism for controlling the generation of inflammatory mediators from AECs in response to stimulation of cell surface G-protein coupled receptors such as protease-activated and ATP receptors, and are an essential mediator of pulmonary inflammation in diseases such as asthma. We will address this hypothesis through three specific goals: 1) examine the physiological contributions of CRAC channels for allergen- mediated release of ATP and determine how this release stimulates inflammatory cytokines from AECs, 2) investigate the functional interactions between CRAC channels and mitochondrial ROS signaling and assess the impact of this crosstalk for inflammatory cytokine generation, and 3) evaluate the contribution of CRAC channels for mediating airway inflammation in vivo in a mouse model of house dust mite-induced asthma. Together, these studies will advance our understanding of how CRAC channels regulate cellular Ca2+-dependent signaling pathways to modulate allergen-stimulated inflammatory mediators in the airways, and advance the quest for developing novel treatments for allergic airway diseases.