Testosterone decreases and ovarian hormones increase house dust mite-induced dual type 2 and IL-17A-mediated airway inflammation

RATIONALE: Severe asthma prevalence is greater in women compared to men, suggesting sex hormones regulate severe asthma pathogenesis. Patients with severe asthma have increased airway inflammation mediated by type 2 cytokines (IL-4, IL-13, IL-5) and/or IL-17A. We hypothesize that testosterone decreases and ovarian hormones increase type 2 and IL-17A-mediated airway inflammation.

METHODS: House dust mite (HDM) or vehicle was administered intranasally to gonadectomized and sham-operated male and female adult BALB/c mice 4 times per week for 3 weeks. Lungs and bronchoalveolar lavage fluid (BALF) were harvested 24 hours after the last challenge for analysis. Digested lungs cells were restimulated with PMA, ionomycin, and golgi stop. IL-13+ and/or IL-17A+ cells were quantified by flow cytometry.

RESULTS: Eosinophils and neutrophils in the BALF and lung IL-13 and IL-17A protein expression were increased in HDM challenged intact female mice compared to HDM challenged intact male mice (n=8-10, p<0.05). CD4 T cells accounted for >50% of IL-13+ or IL-17A+ cells in HDM challenged mice (n= 7-10, p<0.05). The IL-13+ and IL-17A+ CD4 T cells as well as IL-17A+ γδ T cells were increased in HDM challenged gonadectomized male mice and sham-operated female mice compared to HDM challenged sham-operated male and gonadectomized female mice (n=7-10, p<0.05). HDM challenged sham-operated female mice and gonadectomized male mice had increased IL-13+ ILC2 compared to HDM challenged sham-operated male mice (n=6-8, p<0.05).

CONCLUSIONS: Testosterone decreased and ovarian hormones increased eosinophil and neutrophilic inflammation and IL-13 and IL-17A production. These results provide a potential explanation for the increased prevalence of women with severe asthma.