Interactions between lung microenvironment and immune responses in the sex-specific manifestation of asthma

• Applicant: Dr. Dimitra Zazara
• Subject Area: Immunology ; Pediatric and Adolescent Medicine
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 429191104

Asthma is a chronic inflammatory airway disease with an increasing prevalence worldwide. Striking sex-specific and age-dependent differences have been described in asthma prevalence and manifestation. While boys are mostly affected until puberty, this bias reverses in adolescence and adulthood when sex hormones begin to surge and females become more affected. Additionally, we and others have previously reported that the lung microenvironment and specifically the respiratory epithelium play an integral role in the observed sex bias in childhood asthma. These observations suggest that both sex hormones and the lung microenvironment contribute to the asthma-related sex bias. Apart from the respiratory epithelium, immune cells permanently residing in the lung, comprising the so-called tissue-resident immunity, are also essential parts of the lung microenvironment and may be implicated in this context. Despite mounting evidence highlighting sex differences in circulating immunity, little is known about potential sex-specific traits of tissue-resident immunity and their potential alterations across the lifespan. We have recently identified a sexual dimorphism in both innate and adaptive tissue-resident immunity of the naïve mouse lung, which was established and further intensified with age progression. Of note, androgens were identified as a key determinant of the observed sex bias, since androgen level modulation profoundly affected lung-resident immunity in both male and female mice. Importantly, no alterations were observed upon oestrogen level modulation. The sexual dimorphism of lung-resident immunity and the role of androgens in this context may explain the sex bias observed in asthma manifestation. Importantly, given the age-related fluctuations in sex hormone levels, age-specific sex differences in lung tissue-resident immunity may potentially contribute to the shifting sex bias in asthma manifestation. Using mouse models for hormone manipulation, orthotopic lung transplantation, and experimental asthma induction, we here aim to investigate the interaction of androgens with the lung microenvironment, including lung-resident immunity and airway epithelium, and ist role in the age-dependent sexual dimorphism of asthma across the lifespan. Taken together, this study will provide new insight in the mechanisms underlying sex-specific differences in asthma, and set the basis for the design of tailored treatment strategies that take the existing sexual dimorphism of the lung microenvironment into account.

• DFG Programme: Research Units
• Subproject of: FOR 5068: Sex differences in immunity