Influence of sex chromosome and gonadal sex on lung immune cell responses following allergen exposure

Males and females exhibit distinct immunological responses to allergen exposure. However, limited data exist regarding the role of sex in allergic asthma. The Four Core Genotype (FCG) mouse model offers a novel approach to disentangling the effects of sex chromosomes and sex hormones in physiological effects. Prior research suggests that female gonadal hormones exacerbate asthma phenotypes while male hormones are protective. Based on this, we hypothesized that sex differences in the inflammatory and immune responses in allergic asthma are primarily driven by sex hormones, rather than sex chromosome effects. To examine the role of sex chromosomes and gonadal hormones in allergic airway inflammation, we used a well-established FCG mouse model of allergic airway inflammation. Mice aged 8–10 weeks (n=5–10 per group) were intranasally challenged with house dust mite allergens (HDM from Dermatophagoides pteronyssinus and Dermatophagoides farina ) for 5 days/week over 5 weeks, or controls (PBS). Lung tissue was harvested 72 hours post-final exposure and analyzed via flow cytometry. The interaction of sex chromosomes, gonadal hormones, and treatment was evaluated using two-way ANOVA. Genotype significantly influenced immune cell responses. Alveolar macrophages were elevated in mice with female sex chromosomes and male gonads (XXM) post-HDM exposure, showing a significant genotype-treatment interaction (P=0.0001). Eosinophils were increased in HDM-treated mice with female sex chromosomes and gonads (XXF) (P=0.0028), while CD103+ dendritic cells were higher in XXM mice (P=0.0001). CD11b+ dendritic cells were elevated in HDM-treated mice with male chromosomes and gonads (XYM) (P=0.01), driven mainly by treatment effects. Analysis by sex chromosomes revealed higher CD11b+ dendritic cells in HDM-treated mice with male chromosomes (XY) (P=0.0073) and mice with female chromosomes (XX) (P=0.0043) compared to controls. Significant effects of sex chromosomes were observed in CD11b+ dendritic cells, interstitial macrophages, B-cells, neutrophils, and CD4+ T cells. Grouping mice with the same gonads showed increased alveolar macrophages, eosinophils, and CD4+, and CD8+ T cells in HDM-treated mice with female gonads (XXF, XYF), while CD103+ dendritic cells, plasmacytoid dendritic cells, and B-cells were reduced. Treatment effects were significant for eosinophils, while hormones independently influenced various immune cells, including NKT cells, B-cells, and T cells. The study highlights that genotype, sex chromosomes, and sex hormones significantly influence lung immune cell populations after allergen exposure. Genotype strongly impacted alveolar macrophages, eosinophils, and CD103+ dendritic cells, while sex chromosomes influenced CD11b+ dendritic cells and other immune cells. Hormones independently modulated multiple immune responses, particularly eosinophils, underscoring their key role in allergic asthma. NIH/NHLBI, Grant/Award Number: R01HL159764 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.