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

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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.