Sex chromosomes and gonadal sex interactions in airway and immune responses to allergen challenge

Asthma is a chronic respiratory condition influenced by genetic, environmental, and sex-related factors. Women experience greater asthma severity, airway hyperresponsiveness (AHR), and inflammation than men, likely due to sex-linked genetic and hormonal differences. However, the independent contributions of sex chromosomes and gonadal sex to these responses remain unclear. This study examines their roles in allergic airway responses using the four core genotype (FCG) mouse model, which distinguishes between chromosomal and gonadal influences. We hypothesized that XX-mice and those with female gonads would exhibit heightened airway inflammation and immune activation in response to house dust mite (HDM) challenge. Using a controlled, moderate 5-wk HDM exposure paradigm that reliably induced allergic airway inflammation, we aimed to capture biologically relevant sex- and genotype-dependent variations rather than a maximal inflammatory phenotype. FCG mice (XXF, XXM, XYF, and XYM) underwent 5 wk of HDM exposure, followed by assessments of airway lung function and inflammation. Our results showed that HDM challenge differentially increased airway resistance and elastance in FCG mice, with specific contributions of sex chromosomes and gonadal sex. Histological analysis showed higher lung inflammation and goblet cell hyperplasia in challenged mice with female gonads than in those with male gonads. Flow cytometry assessment revealed elevated eosinophils in XXF mice. Combined, our findings show that both sex chromosomes and gonadal sex influence airway inflammation and immune responses to allergen challenge, with mice bearing XX chromosomes and female gonads exhibiting greater susceptibility.<b>NEW & NOTEWORTHY</b> This study provides new insights into how sex chromosomes and gonadal sex independently and interactively shape immune cell responses during allergic airway inflammation. Using the four core genotype (FCG) mouse model, we show that both genetic and hormonal factors significantly influence pulmonary immune cell populations after allergen exposure. These findings advance our understanding of the biological basis for sex differences in asthma and highlight the need for sex-informed approaches in respiratory disease research and therapy development.