Environmental Pollutants Potentiate Allergic Inflammation via Functional Axis of Aryl hydrocarbon Receptor, ROS, and CaMKII in Asthma

摘要 在过去的十年里，哮喘变得越来越常见。共同接触环境污染物和 过敏原可加重过敏性致敏，并诱发严重哮喘的关键特征。蟑螂 是一种有效的过敏原来源，可诱导过敏并引发过敏性呼吸道症状。 有趣的是，接触多环芳烃(PAHs)，这是柴油排放的颗粒物 (DEPS)衍生的毒素，会增加患蟑螂过敏和哮喘的可能性。然而， 潜在的分子机制目前还不是很清楚。我们的长期目标是阐明 环境污染物增强蟑螂变态反应性炎症的基本机制 并确定过敏性哮喘的新治疗靶点。我们更具体的目标是解决这个假说 肥大细胞募集和功能的改变在这方面的积极作用迄今还未得到充分认识。 环境污染物与呼吸道过敏性炎症的相互作用。芳香烃受体(AhR) 是常见环境污染物的受体。AHR已被证明是驾驶过程中的一个关键受体 环境污染物--加重过敏性肺部炎症。我们最近在以下方面做出了重大贡献 阐明AhR信号在肥大细胞激活和变态反应性炎症中的作用。我们是第一个 钙调素依赖的蛋白激酶II(ox-CaMKII)氧化激活在血管内皮细胞中的重要作用 AHR介导肥大细胞活化和ROS产生。此外，最近的发现表明 线粒体靶向抑制呼吸道上皮细胞CaMKII抑制线粒体ROS的产生和 预防过敏性哮喘。因此，这些发现提出了CaMKII是感知到 “上游”ROS和控制“下游”线粒体ROS的产生，肥大细胞的激活和 过敏性哮喘的特征。这些令人兴奋的新数据为检验我们的核心假设奠定了基础： AHR介导环境污染物增强型变应原诱导的线粒体ROS生成和氧化 CaMKII的激活在肥大细胞激活和过敏性哮喘的发生发展中起着至关重要的作用。三 提出了既独立又相关的具体目标。目标1提出研究以确定上皮性AhR 在环境污染物增强型变应原诱导上皮线粒体ROS中的作用 哮喘中肥大细胞的产生、细胞因子的释放和肥大细胞的募集。目标2提出实验来定义 肥大细胞表面AHR介导环境污染物增强型变应原诱导的线粒体CaMKII 参与ROS的产生和CaMKII的氧化激活。目标3建议进行研究以阐明这一角色 CaMKII氧化活化在肥大细胞活化和过敏性哮喘中的作用及其可能机制的探讨 机械装置。拟议的研究具有重要意义，因为它将提供一个概念性框架，将 环境污染物/变应原-AhR-ROS-OX-CaMKII轴对肥大细胞激活与过敏性疾病发展的影响 哮喘。这些研究可能最终允许开发新的过敏性哮喘治疗靶点。

ABSTRACT Asthma has become increasingly common in the past decade. Co-exposure to environmental pollutants and allergens can exacerbate allergic sensitization and induce key characteristics of severe asthma. Cockroaches are a potent source of allergen that can induce sensitization and drive allergic respiratory symptoms. Interestingly, exposure to polycyclic aromatic hydrocarbons (PAHs), which are diesel exhaust particulates (DEPs)-derived toxins, can increase the likelihood of developing cockroach allergy and asthma. However, the underlying molecular mechanisms are currently not well-established. Our long-term goals are to elucidate the fundamental mechanisms by which environmental pollutants enhance cockroach-induced allergic inflammation and identify novel therapeutic targets for allergic asthma. Our more specific aims are to address the hypothesis that alterations in recruitment and function of mast cells play a heretofore underappreciated role in the positive interactions between environmental pollutants and airway allergic inflammation. Aryl hydrocarbon receptor (AhR) is a receptor for common environmental contaminants. AHR has been shown to be a key receptor in driving environmental pollutant-enhanced allergic lung inflammation. We have recently made significant contributions to unraveling the function of AhR signaling in mast cell activation and allergic inflammation. We were the first to characterize the essential role of oxidative activation of calmodulin-dependent protein kinase II (ox-CaMKII) in AhR mediated mast cell activation and ROS production. Furthermore, recent discoveries suggest that mitochondrial-targeted inhibition of CaMKII in airway epithelium suppresses mitochondrial ROS generation and protects against allergic asthma. Thus, these findings raise the possibility that CaMKII is a central player sensing “upstream” ROS and controlling “downstream” mitochondrial ROS generation, mast cell activation and characteristic features of allergic asthma. These exciting new data set the stage to test our central hypothesis: AhR mediates environmental pollutant-potentiated allergen-induced mitochondrial ROS generation and oxidative activation of CaMKII, which are essential for mast cell activation and development of allergic asthma. Three independent yet related specific aims are proposed. Aim 1 proposes studies to determine whether epithelial AhR plays a role in mediating environmental pollutant-enhanced allergen-induced epithelial mitochondrial ROS generation, cytokine release, and mast cell recruitment in asthma. Aim 2 proposes experiments to define whether AhR on mast cells mediates environmental pollutant-enhanced allergen-induced mitochondrial CaMKII that contributes to ROS generation and oxidative activation of CaMKII. Aim 3 proposes studies to elucidate the role of oxidative activation of CaMKII in mast cell activation and allergic asthma and to explore the possible mechanisms. The proposed research is significant as it will provide a conceptual framework linking the environmental pollutant/allergen-AhR-ROS-ox-CaMKII axis to mast cell activation and development of allergic asthma. These studies may ultimately allow for the development of new therapeutic targets for allergic asthma.