Estrogen receptor β regulates sex‐dependent airway mechanics and inflammation in a murine model of allergen exposure

Abstract Sex differences in asthma severity have been reported; however, the specific contribution of estrogen receptor β (ERβ) remains incompletely defined. We tested the hypothesis that ERβ modulates sex‐specific physiological responses to chronic allergen exposure using C57BL/6J wild‐type (WT) and ERβ‐deficient (Esr2 − / − ) male and female mice subjected to 5 weeks of house dust mite (HDM) challenge. Lung mechanics were assessed using flexiVent and integrated with histopathology and whole‐lung transcriptomics. We found that HDM exposure increased total respiratory resistance (Rrs), Newtonian resistance (Rn), and tissue elastance (H), with the greatest impairment in female Esr2 − / − mice, significantly exceeding WT females. These changes were accompanied by marked peribronchial inflammation and mucus metaplasia, particularly in females. ERβ deficiency also produced compartment‐specific effects. Transcriptomic analyses revealed disruption of epithelial differentiation, immunoglobulin gene expression, and metabolic pathways, with downregulation of humoral and epithelial programs in Esr2 − / − females. Collectively, these findings identify ERβ as a critical determinant of sex‐specific airway mechanics and inflammatory remodeling during allergen exposure. We conclude that ERβ protects the female lung from exaggerated functional decline, mucus metaplasia, and tissue stiffening, while exerting distinct spatial and immunological effects in males, highlighting ERβ signaling as a target for sex‐informed asthma therapeutics.