Sex differences in lung-resident immunity are modulated by androgen-dependent pathways

Background: Sex differences in the manifestation of respiratory diseases have been reported and attributed to sexually dimorphic immune responses. The role of lung-resident immunity in this context remains elusive. Aims: Here, we aimed to examine the sex differences in lung-resident immunity and the role of sex hormones in this context. Methods: Using flow cytometry, we characterized lung-resident immunity in adult C57BL/6 female and male mice, both before and after hormone modulation approaches, such as ovariectomy, castration or testosterone supplementation in females. Finally, the impact of hormones was also examined using mouse orthotopic lung transplantation. Results: Increased alveolar macrophages and lung-resident monocytes were found in male mice, while female mice exhibited higher lung-resident dendritic cells. Castration reversed these effects, as reduced monocytes and alveolar were detected in castrated compared to control males. Castrated males also exhibited increased B cells compared to control males. Of note, no differences in lung-resident immunity were seen after ovariectomy, while testosterone supplementation of female mice was associated with increased neutrophils and decreased B cells residing in the lung. Sex-mismatched orthotopic lung transplantation supported the impact of androgens on lung-resident immunity, as lungs from female donors exhibited reduced resident B cells after their transplantation into male recipients. Conclusions: Our findings highlight that the sexual dimorphism of lung-resident immunity is modulated by androgen-dependent pathways and set the basis for further studies focusing on sex differences in respiratory immune diseases.