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

摘要 哮喘在过去十年中变得越来越普遍。共同接触环境污染物， 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 是一种潜在的过敏原来源，可诱导致敏并引发过敏性呼吸道症状。 有趣的是，暴露于多环芳烃（PAH），这是柴油机废气颗粒 （DEPs）衍生的毒素，可以增加发展蟑螂过敏和哮喘的可能性。但 潜在的分子机制目前还没有很好地建立。我们的长期目标是阐明 环境污染物增强蟑螂诱导的过敏性炎症的基本机制 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假设 肥大细胞的募集和功能的改变在正性免疫反应中起着迄今为止未被充分认识的作用。 环境污染物和气道过敏性炎症之间的相互作用。芳香烃受体（AhR） 是常见环境污染物的受体。AHR已被证明是驾驶中的关键受体 环境污染物增强的过敏性肺部炎症。最近，我们为以下方面作出了重大贡献： 阐明AhR信号传导在肥大细胞活化和过敏性炎症中的功能。我们是第一个 表征钙调蛋白依赖性蛋白激酶II（ox-CaMKII）的氧化活化在 AhR介导肥大细胞活化和ROS产生。此外，最近的发现表明， 气道上皮细胞中CaMKII的靶向抑制可抑制线粒体ROS生成， 预防过敏性哮喘。因此，这些发现提高了CaMKII是感知 “上游”ROS和控制“下游”线粒体ROS生成、肥大细胞活化和 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介导环境污染增强的变应原诱导的线粒体ROS产生和氧化 CaMKII的活化，其对于肥大细胞活化和过敏性哮喘的发展是必需的。三 提出了独立但相关的具体目标。目的1提出研究，以确定上皮AhR是否 在介导环境污染物增强的变应原诱导的上皮线粒体ROS中起作用 哮喘中肥大细胞的生成、细胞因子释放和肥大细胞募集。目标2提出实验来确定是否 肥大细胞上的AhR介导环境污染物增强的变应原诱导的线粒体CaMKII， 有助于ROS的产生和CaMKII的氧化活化。目标3提出了研究来阐明 氧化激活CaMK Ⅱ在肥大细胞活化和过敏性哮喘中的作用，并探讨其可能 机制等拟议的研究是重要的，因为它将提供一个概念框架， 环境污染物/过敏原-AhR-ROS-ox-CaMKII轴对肥大细胞活化和过敏性疾病发展的影响 哮喘这些研究可能最终允许开发过敏性哮喘的新治疗靶点。

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.