McKernan, K. E. | Search bioRxiv

bioRxiv2025

Ovarian Hormones and Obesity Drive Th17-mediated Airway Inflammation through Estrogen Receptor Signaling

Obesity is a risk factor for increased prevalence and severity of asthma, particularly in females. As adults, females have increased prevalence of asthma compared to 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-) in T cells increased airway inflammation in the context of obesity. To test our hypothesis, we utilized a high fat (HFD) on female and male mice that underwent ovariectomy or gonadectomy or in Esr1fl/fl X Cd4Cre+ male and female mice. As controls, mice in similar groups were fed normal chow. After 8-12 weeks on diets, house dust mite (HDM) sensitization and challenge occurred in all mice. Lungs and BAL fluid were harvested 24 hours after the last challenge. Ovarian hormones and ER- signaling in T cells increased eosinophils, neutrophils, and Th17-mediated airway inflammation in the lungs of obese female mice. Additionally, using PBMCs from a well-characterized obese asthma cohort, we determined that obese women with asthma had increased Th17 cells compared to obese men with asthma. Our results show that ER- 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 to men with asthma. Further research into the interplay between hormonal signaling and immune responses in asthma is essential for developing personalized treatments. One Sentence SummaryEstrogen receptor-alpha signaling, in the context of obesity, increases allergen-induced Th17-mediated airway inflammation in female mice.

immunology↗

bioRxiv2024

Single cell profiling to determine influence of wheeze and early-life viral infection on developmental programming of airway epithelium

AO_SCPLOWBSTRACTC_SCPLOWAlthough childhood asthma is in part an airway epithelial disorder, the development of the airway epithelium in asthma is not understood. We sought to characterize airway epithelial developmental phenotypes in those with and without recurrent wheeze and the impact of infant infection with respiratory syncytial virus (RSV). Nasal airway epithelial cells (NAECs) were collected at age 2-3 years from an a priori designed nested birth cohort of children from four mutually exclusive groups of wheezers/non-wheezers and RSV-infected/uninfected in the first year of life. NAECs were cultured in air-liquid interface differentiation conditions followed by a combined analysis of single cell RNA sequencing (scRNA-seq) and in vitro infection with respiratory syncytial virus (RSV). NAECs from children with a wheeze phenotype were characterized by abnormal differentiation and basal cell activation of developmental pathways, plasticity in precursor differentiation and a delayed onset of maturation. NAECs from children with wheeze also had increased diversity of currently known RSV receptors and blunted anti-viral immune responses to in vitro infection. The most dramatic changes in differentiation of cultured epithelium were observed in NAECs derived from children that had both wheeze and RSV in the first year of life. Together this suggests that airway epithelium in children with wheeze is developmentally reprogrammed and characterized by increased barrier permeability, decreased antiviral response, and increased RSV receptors, which may predispose to and amplify the effects of RSV infection in infancy and susceptibility to other asthma risk factors that interact with the airway mucosa. SUMMARYNasal airway epithelial cells from children with wheeze are characterized by altered development and increased susceptibility to RSV infection.

developmental biology↗