Club cell-derived brain-derived neurotrophic factor regulates murine airway mechanics and mucin production in response to IL-13 in a sex-dependent manner.

INTRODUCTION: Brain-derived neurotrophic factor (BDNF) is a neural plasticity molecule that is increasingly recognized for its role in airway pathophysiology, including diseases like asthma. Although many cells in the airway can produce BDNF, our understanding of epithelial-derived BDNF and its role in airway health and disease remains limited. METHODS: In the current study, we studied male and female mice with conditional loss of Bdnf in airway club cells and challenged them intranasally with saline (vehicle control) or interleukin 13 (IL-13) for 4 days. We measured pulmonary mechanics and the abundance and secretion characteristics of the major secreted mucin glycoproteins, mucin 5B (Muc5b) and mucin 5ac (Muc5ac). RESULTS: Female mice with conditional loss of club cell Bdnf showed increased Muc5b protein in the airway epithelia under basal and IL-13-stimulated conditions compared to female mice with intact Bdnf. In contrast, conditional loss of club cell Bdnf in male mice augmented whole-lung Muc5ac mRNA levels under basal and IL-13-stimulated conditions. IL-13-treated female mice with conditional loss of club cell Bdnf showed decreased airway elastance in response to increasing concentrations of nebulized methacholine, suggesting that loss of club cell Bdnf had a protective effect. No statistically significant differences were observed in pulmonary mechanics between male mice with or without conditional loss of epithelial cell Bdnf, although treatment effects of IL-13 were noted. Mechanistic and complementary studies performed in NCI-H322 cells, a human cell line with "club cell-like" characteristics, failed to demonstrate a relationship among BDNF, IL-13 signaling, and Muc5ac at the mRNA level. CONCLUSION: These data highlight sex-dependent differences and club cell-specific effects of Bdnf in regulating airway physiology under inflammatory conditions in mice, suggesting that further studies are needed to understand potential translational implications.