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

环境污染物通过芳基烃受体、ROS 和 CaMKII 功能轴在哮喘中加剧过敏性炎症

• 批准号: 10161717
• 负责人: Peisong Gao
• 金额: $ 57.74万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-19 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10161717
• 关键词: Address; Adenoviruses; Allergens; Allergic; Allergic inflammation; Aromatic Polycyclic Hydrocarbons; Aryl Hydrocarbon Receptor; Asthma; Automobile Driving; Characteristics; Conditioned Culture Media; Cost Measures; Data Set; Development; Dictyoptera; Diesel Exhaust; Economic Burden; Environmental Pollutants; Environmental Pollution; Epithelial; Exposure to; Extrinsic asthma; Generations; Goals; Hypersensitivity; In Vitro; Knockout Mice; Link; Longitudinal Studies; Lung; Lung Inflammation; Mediating; Mitochondria; Molecular; Mus; Oxidants; Particulate; Patients; Play; Prevalence; Production; Protein Isoforms; Public Health; Receptor Signaling; Research; Resistance; Respiratory Signs and Symptoms; Role; Source; System; Testing; Therapeutic; Toxin; airway epithelium; allergic airway inflammation; base; calmodulin-dependent protein kinase II; cell motility; cytokine; environmental allergen; experimental study; in vivo Model; innovation; knock-down; mast cell; mouse model; new therapeutic target; novel; prophylactic; receptor; recruit; respiratory; tool

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.

抽象的 在过去的十年中，哮喘变得越来越普遍。共同暴露于环境污染物和 过敏原会加剧过敏性传感化并影响严重哮喘的关键特征。蟑螂 是可能引起灵敏度并驱动过敏性呼吸道症状的潜在过敏原来源。 有趣的是，暴露于柴油排气颗粒的多环芳烃（PAHS）（PAHS） （DEPS）衍生的毒素可以增加蟑螂过敏和哮喘的可能性。但是， 目前，潜在的分子机制尚不确定。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注射的基本机制 并确定过敏性哮喘的新型热靶标。我们更具体的目的是解决该假设 肥大细胞的募集和功能的改变在阳性中扮演着迄今为止的作用不足 环境污染物与气道过敏注射之间的相互作用。芳基烃受体（AHR） 是常见环境污染物的受体。 AHR已被证明是驾驶的关键受体 环境污染物增强过敏性肺部感染。我们最近为 阐明肥大细胞激活和过敏性注射中AHR信号的功能。我们是第一个 表征钙调蛋白依赖性蛋白激酶II（OX-CAMKII）氧化激活的基本作用 AHR介导的肥大细胞激活和ROS产生。此外，最近的发现表明 线粒体靶向CAMKII在气道上皮抑制抑制线粒体ROS和 预防过敏性哮喘。这是这些发现提出了Camkii是中央播放器传感器的可能性 “上游” ROS并控制“下游”线粒体ROS的产生，肥大细胞激活和 过敏性哮喘的特征。这些令人兴奋的新数据为测试我们的中心假设奠定了基础： AHR介导环境污染物启用过敏原诱导的线粒体ROS的产生和氧化 CAMKII的激活，这对于肥大细胞激活和过敏性哮喘的发育至关重要。三 提出了独立但相关的特定目标。 AIM 1提案研究以确定上皮AHR是否 在介导环境污染物增强过敏原诱导的上皮线粒体ROS中起作用 哮喘中的产生，细胞因子释放和肥大细胞募集。目标2提案实验以定义是否 肥大细胞上的AHR介导环境污染物增强的过敏原诱导的线粒体CAMKII 有助于ROS的产生和CAMKII的氧化激活。 AIR 3提案研究以阐明角色 肥大细胞激活和过敏性哮喘中CaMKII的氧化激活，并探索可能 机制。拟议的研究非常重要，因为它将提供一个概念框架，将 环境污染物/过敏原-AHR-ROS-OX-CAMKII轴对肥大细胞激活和发育过敏 哮喘。这些研究最终可能允许开发过敏性哮喘的新治疗靶标。