Male sex hormones alter lung nerves to reduce allergic inflammation in mice, according to a study led by researchers at Zhejiang University.
The findings, published in the academic journal Science, offer a potential biological explanation for a long-standing medical mystery surrounding asthma and gender.
Doctors have long observed a clear shift in how asthma affects males and females across different stages of life. During childhood, allergic asthma occurs more frequently in boys than in girls. However, that pattern reverses after puberty, when the condition becomes significantly more common in adult women.
Allergic asthma is a chronic respiratory condition in which the airways become inflamed and narrow when exposed to environmental triggers such as house dust mites, pollen, or animal dander. Zhejiang University, a leading public research university located in Hangzhou, China, led the research team investigating the hormonal driver behind this disparity.
Sex differences in allergic response
To examine the relationship between hormones and respiratory allergies, a team led by researcher Jing Yang conducted experiments on mice. The animals were exposed to house dust mites, a standard allergen used in laboratory settings to reproduce the characteristic features of allergic asthma.
Female mice in the study developed a markedly stronger type 2 inflammatory response compared to male mice. The lungs of female mice accumulated higher numbers of eosinophils, which are disease-fighting white blood cells that drive allergic inflammation, alongside type 2 innate lymphoid cells, known as ILC2.
The researchers also observed elevated concentrations of several key inflammatory signaling molecules in female lungs, specifically the cytokines IL-4, IL-5, and IL-13. Innate lymphoid cells play a critical role in allergic responses by maintaining type 2 immunity and releasing signals that recruit eosinophils into the airways.
Role of testosterone and gonads
The researchers found that the difference in allergic response between the sexes largely disappeared when they surgically removed the gonads of the mice prior to allergen exposure. Gonads are the primary reproductive glands that produce sex hormones such as testosterone and estrogen.
When the team administered testosterone to the mice whose gonads had been removed, the infiltration of immune cells and the production of inflammatory molecules dropped again. Testosterone is the primary male sex hormone, belonging to a group of steroid hormones known as androgens.
The experimental results indicated that male sex hormones were directly responsible for suppressing the heightened allergic response seen in female animals.
Impact on lung nerve fibers
Yang and the research team discovered that androgens do not act solely on immune cells. They also directly influence nerve cells located inside lung tissue.
These pulmonary neurons express androgen receptors, which are specialized proteins that allow nerve cells to detect and respond to male sex hormones. Analysis of the neurons revealed significant changes in the expression of genes involved in neuronal development.
Male mice with intact sex hormones exhibited a noticeably higher density of sympathetic nerve fibers in their lung tissue than animals whose gonads had been removed. The sympathetic nervous system is the branch of the autonomic nervous system that regulates involuntary bodily functions and stress responses.
To confirm the importance of these neural pathways, the authors specifically deleted androgen receptors from sympathetic neurons in a group of mice. When exposed to dust mites, these modified mice accumulated more eosinophils, produced higher levels of inflammatory signals, and displayed increased airway hyperreactivity, a condition where bronchial passages contract too easily.
Noradrenaline and immune suppression
The critical biological link connecting the nervous system to lung inflammation is noradrenaline, also known as norepinephrine. Noradrenaline is an essential neurotransmitter released by sympathetic nerve fibers to transmit signals across nerve junctions.
Sympathetic fibers in the lung release noradrenaline, while nearby immune cells express receptors designed to receive the signal. In direct laboratory tests on ILC2 cells, the researchers confirmed that noradrenaline reduced the production of IL-5, the specific cytokine responsible for recruiting inflammatory eosinophils into airway tissue.
The study outlines a complete biological chain of events: androgens activate receptors on sympathetic neurons, promoting a denser nerve network in the lungs. These nerve fibers release noradrenaline, which acts directly on immune cells to quiet the allergic inflammatory response.
Therapeutic implications for humans
The surge in sex hormones during puberty could explain why allergic inflammation decreases in some males as they mature. However, the authors noted that testosterone is not the only factor involved, pointing out that female sex hormones can also alter immune responses and airway function.
The researchers emphasized that the findings do not mean testosterone can currently be used as an asthma treatment. All experiments were conducted strictly in mice, and further studies are required to determine whether the exact same neural circuit operates in humans.
In addition, administering sex hormones systemically would trigger widespread side effects across multiple organ systems. Instead, future therapeutic strategies could focus on targeting specific components of the pathway, such as the nerve-to-noradrenaline connection, without requiring direct hormone administration.
