Macrophages in steroid resistant asthma

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PROJECT SUMMARY Pediatric asthma is a chronic pulmonary inflammatory disease that is causes airway inflammation and restricted airflow. Patients with severe asthma are resistant to steroid treatment, which leads to worsened symptoms and exacerbations. While asthma is known to involve T-helper 2 (Th2) inflammation, recent studies suggest steroid resistant asthmatics have a predominant Th1 inflammatory profile, involving IFNγ and Th1 lymphocytes. Although the adaptive immune response has been shown to mediate steroid resistance in asthma, the contributions of the innate immune cells, such as macrophages are not well understood. Lung macrophages, either classically- or alternatively-activated, are known to produce and secrete cytokines that are involved in Th2 and Th1 inflammation, making them highly relevant to asthma pathogenesis. Previous studies have shown that macrophages have an important role in asthma, yet little is known about macrophage contributions to steroid resistance and severe asthma. Using an augmented ovalbumin mouse model and primary mouse and human macrophages, we will investigate macrophages and their contributions to airway inflammation, airway and hyperresponsiveness in 2 Specific Aims. Studies in Aim 1 will determine the role of steroid resistant lung macrophages in a mouse model of allergic airway inflammation using lung macrophage depletion and adoptive transfer techniques. In Aim 2, this proposal will examine the mechanisms by which IRF5, a pro-inflammatory transcription factor, disrupts glucocorticoid receptor signaling in classically-activated macrophages. These studies will be conducted using cultured primary mouse bone marrow derived macrophages. To further assess steroid resistant pathways in lung macrophages, RNA-seq analysis will be performed. Additionally, steroid sensitivity will also be assessed in classically-activated human lung macrophages. Importantly, these studies are supplemented with a comprehensive postdoctoral training plan that will enhance the scientific and professional development of a promising postdoctoral fellow. The concepts and skills learned will provide a foundation for future pathway to independence grants such as the K99/R00.