Severe asthma is a significant health care concern, with patients having poorer asthma control, poorer lung function, and increased health care costs compared to milder asthma phenotypes. A sexual dimorphism also exists in severe asthma, and as adults, women are twice as likely as men to have severe asthma. Increased type 2 cytokines and/or IL-17A, leading to increased airway eosinophil and neutrophils, respectively, are associated with asthma. Previous studies showed that ovarian hormones increased while testosterone decreased type 2 OR IL-17A-mediated inflammatory responses. However, the mechanisms by which sex hormones mediated dual type 2 cytokines and IL-17A inflammatory responses remained unclear. We hypothesized that during dual type 2 and IL-17A mediated airway inflammation, ovarian hormones promote inflammation by increasing cytokine expression of type 2 cytokines and IL-17A while testosterone attenuates inflammation by decreasing cell numbers of type 2 and IL-17A secreting cells. To test our hypothesis, we utilized a house dust mite (HDM) model of airway inflammation in hormonally intact or deficient female and male mice and determined how sex hormones affected total numbers and cytokine expression from CD4+ T helper cell subsets important for type 2 inflammation (Th2 cells) or IL-17A-mediated inflammation (Th17 cells). Ovarian hormones increased and testosterone decreased HDM-induced IL-13+Th2 cells and IL-17A+ Th17 cells, but through different mechanisms. Subsequent studies using ERα and AR deficient mice determined that ERα signaling increased IL-23R surface expression on Th17 cells, leading to increased IL-17A protein expression. However, AR signaling intrinsically decreased total numbers of IL-17A+ Th17 cells in the lung and decreased Il23r mRNA and IL-17A protein expression in Th17 cells. Combined, these findings showed that sex hormones signaling regulates type 2 and IL-17A-mediated airway inflammation and IL-17A expression in Th17 cells, providing potential mechanisms for the increased prevalence of asthma in women compared to men.
|Advisor:||Rathmell, Jeffrey C.|
|Commitee:||Major, Amy S., Matusik, Robert J., Peebles, R. Stokes, Newcomb, Dawn C.|
|Department:||Microbiology and Immunology|
|School Location:||United States -- Tennessee|
|Source:||DAI-B 82/9(E), Dissertation Abstracts International|
|Subjects:||Immunology, Cellular biology, Biochemistry, Health care management, Public health|
|Keywords:||Androgen receptor, Asthma, Estrogen receptor alpha, Ovarian hormones, Testosterone, Type 2 cytokines and IL-17A|
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