Sex hormones influence ORMDL3 expression: Implications for sex-associated asthma phenotype

Area of Science:

• Immunology
• Genetics
• Respiratory Medicine

Background:

• Asthma exhibits significant sex differences in prevalence and severity, with underlying molecular mechanisms poorly understood.
• Genetic variations in sphingolipid metabolism, particularly the ORMDL3 gene, are linked to asthma risk.

Purpose of the Study:

• To investigate the role of ORMDL3 in sex-based disparities in airway function and asthma-like symptoms.
• To explore the influence of estrogen and allergens on ORMDL3 expression and related pathways.

Main Methods:

• Measured ORMDL3 expression in human lung tissue and bronchial cells exposed to estrogen and allergens.
• Utilized a murine asthma model to assess sex-dependent differences in ORMDL3, airway responsiveness, and remodeling.
• Employed pharmacologic modulation of estrogen and the ORMDL3-sphingosine-1-phosphate (S1P) axis.

Main Results:

• Female lungs showed higher ORMDL3 expression, correlating with lung function.
• Estrogen upregulated ORMDL3 and altered sphingolipid metabolism in airway cells.
• Allergen exposure amplified ORMDL3 expression and airway inflammation, particularly in females.
• In vivo, female mice exhibited increased ORMDL3, S1P, airway hyperresponsiveness, and remodeling, which were partially reversed by estrogen or tamoxifen.
• Inhibition of the ORMDL3-S1P axis specifically attenuated asthma features in female mice.

Conclusions:

• ORMDL3 is an estrogen-responsive gene influencing airway responsiveness.
• Modulation of sphingolipid metabolism by ORMDL3 contributes to sex differences in asthma.
• Estrogen signaling and ORMDL3 pathway present potential therapeutic targets for sex-specific asthma management.