Genetic polymorphisms in sphingolipid metabolism, particularly involving the orosomucoid-like 3 (ORMDL3) gene, have been associated with asthma risk. Notably, asthma prevalence and severity exhibit pronounced sex differences, emerging in childhood and persisting into adulthood. However, the molecular mechanisms underlying this sexual dimorphism remain incompletely elucidated.

We investigated whether ORMDL3 contributes to sex differences in airway function and asthma-like features.

ORMDL3 expression was measured in lung tissues from healthy male and female human donors and in human bronchial epithelial cells (BEAS-2B) after exposure to 17β-estradiol (E2), Dermatophagoides pteronyssinus 1 (Der p 1), or both. A murine preparation of asthma was used to evaluate sex-dependent differences in ORMDL3 expression, airway responsiveness, and remodeling. Pharmacologic modulation of estrogen signaling and the ORMDL3–sphingosine-1-phosphate (S1P) axis were used. Methods included quantitative real-time PCR, immunostaining, liquid chromatography–tandem mass spectrometry, and airway function measurements.

Female lungs exhibited higher ORMDL3 expression than male lungs, and this correlated with elevated forced expiratory volume to forced vital capacity ratios in the same patients. In BEAS-2B cells, E2 significantly upregulated ORMDL3 and altered sphingolipid metabolism by inducing expression of ceramidase, sphingosine kinases 1/2, and S1P receptors. Der p 1 also increased ORMDL3 and triggered epithelial activation via inflammasome signaling, while E2 enhanced IFN-β signaling and MUC5AC expression. Combination Der p 1/E2 synergistically activated sphingolipid, interferon, and inflammasome pathways. These in vitro findings prompted in vivo investigation using a murine asthma preparation, where female mice displayed elevated ORMDL3, sphingosine, and S1P levels, with increased airway hyperresponsiveness and remodeling. Treatment with tamoxifen or E2 normalized airway hyperresponsiveness and S1P signaling across sexes. Allergen sensitization intensified female-biased ORMDL3 expression and airway inflammation. Inhibition of the ORMDL3-S1P axis attenuated asthma-like features only in female animals.

This study identifies ORMDL3 as an estrogen-responsive regulator of airway responsiveness that may contribute to sex-related differences in asthma features through modulation of sphingolipid metabolism.