Why Allergies Strike Men and Women Differently

Across the globe, nearly half of all infants develop wheezing in their first year, which often goes on to become persistent asthma by the age of six.¹ While asthma and other allergic diseases are more common in boys in early childhood, puberty flips the scenario.

Adult women are more prone to allergies and asthma, indicating that sex hormones likely influence the pathogenesis of these conditions.² However, scientists did not fully understand the extent to which sex hormones regulate pulmonary inflammation seen in these situations.

Now, a research team led by Jing Yang, a neuroimmunologist at Peking University, found that male sex hormones dampen allergic responses in mice via the neurotransmitter norepinephrine in the lungs.³ Their findings, published in Science Immunology, reveal an endocrine-neuroimmune axis that drives sex differences in allergic asthma, emphasizing the need to study sex as a biological variable in biomedical research.

For their study, Yang and his team exposed 15-day-old mice to house dust mite extract, an established allergen, for three weeks. Compared to male mice, more immune cells infiltrated the lungs of female mice, who also showed higher cytokine levels, indicating sex differences in allergen-induced pulmonary inflammation.

To investigate the effect of sex hormones on allergic responses, the researchers surgically removed the male animals’ testicles, which produce the male sex hormone androgen. These animals had a higher inflammatory response compared to animals with intact testicles when exposed to the allergen. Treating animals without testicles with male sex hormones before exposing them to the allergen dampened the immune response, validating that androgens suppress allergen-induced lung inflammation.

Yang and his team had previously found that the sympathetic nervous system—which controls the fight-or-flight response—regulates lung inflammation.⁴ Connecting the dots, the researchers observed increased androgen receptor localization in the nerve cell clusters that house sympathetic neurons that innervate the lungs. Comparing RNA sequencing data of this cluster from mice with and without intact testicles indicated that androgen signaling upregulated genes in pathways associated with neuronal development, suggesting that sex hormones may influence how neurons branch out to innervate the lungs.

The researchers next turned to whole-tissue immunolabeling and microscopy and discovered that compared to mice without testicles, control male mice had increased sympathetic neuron density in the lung. This indicated that androgen signaling promotes pulmonary sympathetic innervation. Inactivating androgen signaling in sympathetic neurons heightened allergic inflammation, validating that androgen signaling in these neurons limits allergen-induced inflammation.

Finally, Yang and his team focused on norepinephrine, which is the main neurotransmitter produced by sympathetic neurons. Using fluorescence-activated cell sorting, the researchers isolated white blood cells from mice lungs. Treating these with norepinephrine lowered the cytokine levels, indicating that androgen signaling in sympathetic neurons acts via norepinephrine to dampen allergic reactions in male mice.

The authors noted that these findings lay the foundation to understanding sex differences in asthma, but some gaps in understanding endocrine-mediated neuroimmune interactions remain. For instance, investigating how other hormones like growth hormones, thyroid hormones, and corticosteroids interact with lung-innervating neurons could offer a clearer picture of asthma progression, potentially pointing toward therapeutic targets.