Club Cell Brain-Derived Neurotrophic Factor Regulates Murine Airway Mechanics and Mucin Production in Response to IL-13 in a Sex-Dependent Manner

Amy FaganMariana SponchiadoLuz MataShanil AminJ. Ignacio AguirreSreekala PrabhakaranLeah Renee Reznikov^*

• University of Florida, Gainesville, United States

Brain-derived neurotrophic factor (BDNF) is a neural plasticity molecule that is increasingly recognized for its role in airway pathophysiology, including diseases like asthma. While many cells can produce BDNF in the airway, our understanding of epithelial-derived BDNF and its role airway health and disease is still limited. 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 four days. We measured pulmonary mechanics, as well as the abundance and secretion characteristics of the major secreted mucin glycoproteins, mucin 5B (Muc5b) and mucin 5ac (Muc5ac). 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 Bdnf intact. 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, though 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. These data highlight sex-dependent differences, as well club cell-specific effects, of Bdnf in regulating airway physiology under inflammatory conditions in mice and suggest that further studies are needed to understand potential translational implications.