HMN 2026: How Estrogen-linked IL-33 ramps up lung inflammation

Asthma affects millions of people worldwide, and adult women experience the condition more frequently—and often more severely—than men. Symptoms can also fluctuate during puberty, pregnancy and menopause, yet the biological reasons behind these sex-based differences remain poorly understood. In a study published in Science Immunology, researchers from the Lloyd and Saglani groups at Imperial’s National Heart and Lung Institute (NHLI) have identified a mechanism by which the female sex hormone estrogen can amplify allergic inflammation in the lungs.

Young female mice exposed to house dust mite allergen developed significantly stronger type 2 immune responses—the kind of inflammation typically associated with asthma—including higher levels of immune signaling molecules and increased airway inflammation. These differences appeared after early-life allergen exposure, suggesting how biological sex and associated hormones can shape how the developing immune system responds to environmental triggers.

The researchers then examined which biological signals might underlie the heightened inflammation seen in females. They found that estrogen increased production of IL-33, a molecule known to activate immune cells involved in allergic inflammation. Higher IL-33 levels, in turn, caused increased expression of EGFR—a receptor found on a subset of T helper 2 (TH2) cells. These EGFR-positive cells produced much higher amounts of inflammatory cytokines linked to asthma symptoms.

When the researchers blocked EGFR signaling in female mice, the exaggerated type 2 response was markedly reduced, and the sex-based differences were largely eliminated. Further experiments identified lung fibroblasts, structural cells supporting the airways, as a major source of IL-33 during allergen exposure, with estrogen directly enhancing IL-33 release from these cells.

Insights for understanding asthma severity in women

Although the findings are based on animal studies, the researchers say the results provide insight into how hormones may shape immune responses in the lungs and contribute to sex differences in asthma severity.

The study also highlights IL-33 and EGFR pathways as potential targets for future treatments, particularly for people with “type 2-high” asthma, a form of the disease driven by allergic inflammation. Drugs that block IL-33 are already being tested in clinical trials, and understanding which patients may benefit most could improve personalized approaches to care.

Professor Clare Lloyd, senior author on the study, said, “Asthma severity often changes during periods of hormonal fluctuation, but we still know relatively little about how sex hormones influence immune pathways in the lungs. Our findings suggest that estrogen can amplify allergic inflammation by acting on structural and immune cells together, which may help explain why asthma outcomes can differ between females and males.”

Next steps

The researchers will now investigate whether similar pathways operate in human asthma, including whether IL-33 and EGFR activity differ between males and females at different life stages. A deeper understanding of how hormones interact with immune and structural cells in the lung could help identify new strategies to reduce asthma attacks and improve long-term outcomes.

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