Ovarian hormones and obesity drive Th17-mediated airway inflammation through estrogen receptor-α signaling

Obesity is a risk factor for increased prevalence and severity of asthma, particularly in females. As adults, females have an increased prevalence of asthma compared with males. Yet, the mechanisms remain unclear on how sex hormones and obesity increase airway inflammation. We hypothesize that estrogen signaling through estrogen receptor-alpha (ER-α) in T cells increased airway inflammation in the context of obesity. To test our hypothesis, we utilized a high-fat diet on female and male mice that underwent ovariectomy or gonadectomy or in <i>Esr1</i>^fl/fl <i>X Cd4</i>^Cre+ male and female mice. As controls, mice in similar groups were fed normal chow. After 8-12 wk on diets, house dust mite sensitization and challenge occurred in all mice. Lungs and bronchoalveolar lavage fluid were harvested 24 h after the last challenge. Ovarian hormones and ER-α signaling in T cells increased eosinophils, neutrophils, and Th17-mediated airway inflammation in the lungs of obese female mice. In addition, using peripheral blood mononuclear cells (PBMCs) from a well-characterized cohort of asthmatic participants, we determined that women with asthma and obesity had increased Th17 cells compared with men with asthma and obesity. Our results show that ER-α signaling in T cells increases Th17-mediated airway inflammation in obese mice and that Th17 cells circulate at higher frequencies in women with asthma compared with men with asthma. Further research into the interplay between hormonal signaling and immune responses in asthma is essential for developing personalized treatments.<b>NEW & NOTEWORTHY</b> Estrogen receptor-alpha (ER-α) signaling increased obesity and allergen-induced airway inflammation in mice. In addition, women with obesity and asthma had increased circulating Th17 cells compared with men with obesity and asthma. These findings provide mechanistic insights into the intersection of obesity, sex hormones, and airway inflammation-underscoring the importance of personalized approaches to managing individuals with obesity and asthma.