A Longstanding Clinical Puzzle
Before puberty, boys are more likely than girls to develop asthma. After puberty, the ratio flips: adult women suffer from asthma more frequently and more severely than men, with symptoms often worsening during pregnancy and menopause. Clinicians have suspected that sex hormones drive the shift, but the molecular mechanism has remained elusive. A study from Imperial College London's National Heart and Lung Institute now fills in the missing link.
Published in Science Immunology, the research demonstrates that estrogen increases the production of interleukin-33 (IL-33) in lung fibroblasts, the structural support cells of the airway. Elevated IL-33 in turn boosts the expression of epidermal growth factor receptor (EGFR) on TH2 immune cells, amplifying the type 2 inflammatory cascade that underlies allergic asthma.
The Estrogen-IL-33-EGFR Axis
The discovery emerged from experiments in which young female mice were exposed to house dust mite allergen, a common trigger of human asthma. Compared to age-matched males, the females developed significantly stronger type 2 immune responses, including elevated levels of inflammatory cytokines and increased cellular infiltration of the airways.
Tracing the signal upstream, the researchers found that estrogen acts on fibroblasts in the lung tissue, prompting them to release more IL-33. This alarmin molecule is a known amplifier of type 2 immunity, but its connection to estrogen had not been demonstrated in the lungs before.
IL-33 then signals to TH2 cells, a class of helper T cells that orchestrate allergic inflammation. In the presence of elevated IL-33, TH2 cells upregulate EGFR on their surface. EGFR-positive TH2 cells produce higher quantities of inflammatory mediators, creating a feed-forward loop: more estrogen leads to more IL-33, which arms more TH2 cells with EGFR, which drives more inflammation.
Blocking EGFR Eliminates the Sex Difference
The most striking result came when the researchers blocked EGFR signaling in female mice. The exaggerated type 2 response was markedly reduced, and the sex-based differences in airway inflammation were largely eliminated. In other words, the entire female disadvantage in this model could be traced to a single signaling node.
This finding has immediate therapeutic relevance. EGFR inhibitors are already approved for use in certain cancers, and repurposing them, or developing lung-targeted versions, could offer a new treatment strategy for women with severe, hormone-sensitive asthma.
Implications Across the Lifespan
The estrogen-IL-33-EGFR axis helps explain several clinical observations that have puzzled allergists for decades. The post-pubertal rise in female asthma prevalence coincides with increasing estrogen levels. The worsening of symptoms during pregnancy, when estrogen surges, and the relief some women experience after menopause, when estrogen declines, both fit the model.
It also raises questions about hormone replacement therapy (HRT). If exogenous estrogen amplifies airway IL-33, then HRT could theoretically increase asthma risk in postmenopausal women, a possibility that warrants clinical investigation.
From Mice to Humans
The researchers caution that the findings are based on mouse models and that human validation is essential. They have already begun collecting airway samples from male and female asthma patients at different hormonal stages to test whether the same IL-33 and EGFR patterns hold in human tissue.
If confirmed, the work could usher in a new era of sex-specific asthma management, one that recognizes women's airways as a fundamentally different inflammatory environment and tailors therapy accordingly. For the millions of women worldwide who struggle with poorly controlled asthma, that recognition is long overdue.
