Role of Environmental Factors-Induced Il-17a-Mediated Immune Responses in Asthma Control and Airway Remodeling

There are increasing evidences about the relationship between asthma and environmental factors. Polycyclic aromatic hydrocarbons (PAHs) are major components of particulate matters and traffic-related air pollutants, and may worsen asthma severity by increasing Th2 and Th17 cytokines. Our study revealed that diesel exhaust particles increased the IL-33, IL-25, TSLP and IL-17A mRNA expression and the nuclear translocation of aromatic hydrocarbon receptor (AhR) in primary human epithelial cells. IL-17A also increased the homing of circulating fibrocytes into the airway. Cigarette smoke contains a lot of PAHs that increased expressions of AhR, ILC3, and IL-17A in the nasal tissues of our asthmatics with chronic rhinosinusitis having cigarette smoking. Th17-mediated airway inflammation has a link with mucosa remodeling. Several genes of cytokine promoting Th17 differentiation, IL3 receptor, TSLP receptor, and IL33 receptor had been upregulated in severe asthma. A temperature-controlled laminar airflow (TLA) device has been proved to decrease indoor environment, and significantly reduced exacerbations, and hospitalization in severe asthma. The association between IL-17A-related immune responses, consistent genetic and environmental correlations to asthma control is still poorly understood. In this three-year project, we will recruit people with asthma including (1) High air pollutant area, Severe asthma (n=100) (2) High air pollution area, Asthma NPF (n=100) (3) Low air pollution area, Severe asthma (n=100) (4) Low air pollution area, Asthma NPF (n=100). All subject reside in the region of Taipei, New Taipei city and Taoyuan City. The high air pollution area and low pollution area are defined on the basis of our new grid-scale model of environmental factors established over two years of monitoring. We obtain peripheral blood mononuclear cells to evaluate the Th2, Th17 and Treg paradigm. We obtain bronchial tissue or epithelial cell from bronchial brushing with severe asthma (n=20) and Asthma NPF (n=20) based on high-pollution area and low-air pollution area, and those 20 subjects who receive TLA device for 6 months at next year. Assessment of asthma control, including exacerbation, ACT score and poor compliance, is evaluated by cell phone App system or telephone monitoring. Exhaled NO and pulmonary function test will be performed regularly. Immunohistochemistry for expression of Th2/Th17, ILC2 and ILC3 cells in submucosal cells is determined. The mRNA expression of IL-1β, IL-6, TGF-β1, GM-CSF, MMP-9, IL-17A, IL-25, IL-33, and TSLP in airway tissue is measured. Primary bronchial epithelial cells alone or incubated with fibrocytes are treated with DEP or IL-17A to evaluate the release of IL-17A associated inflammatory cytokines in protein and mRNA level, and fibrocyte proliferation and transformation. Transcriptomic microarray analysis of mRNA for 42 gene sets containing 2431 genes derived from bronchial biopsies will be performed. Topology Data Analysis (TDA) is used to explore clusters driven by gene signatures. Our study incorporates environmental factor-induced IL-17A-mediated immune responses, genotypes and endogenous asthma control factors to determine the precise underlying mechanism of asthma inflammation. Deriving asthma clusters according to differentialy-expressed genes and air pollution exposure may be a better approach to capture the diverse pathways of asthma pathobiology that could offer insights towards achieving personalized medicine.

Project ID:PC10901-0038
External Project ID:MOST107-2314-B182-074-MY3