Dysregulated MUC5B and MUC5AC impair epithelial barrier function and alter granulocyte frequency and activation in the lung and distal sites

BACKGROUND: Mucus obstructs the airways in respiratory diseases where MUC5B is the major gel-forming mucin in COPD and MUC5AC-rich mucus dominates in asthma. Mucin production changes in response to inflammatory signals, but whether mucin dysregulation drives inflammation is less studied. OBJECTIVE: We sought to identify if MUC5B and MUC5AC affect immune cell composition during homeostasis and inflammation. METHODS: mice were assessed by flow cytometry and morphological examination. Epithelial permeability was assessed via intranasal dextran administration, and inflammation was induced by IL-33. Gene expression and inflammatory mediators were analyzed by qPCR and ELISA, respectively. RESULTS: Mucin expression increased with age in WT mice, where Muc5b remained 40 times more abundant than Muc5ac, however, single-mucin deficiency resulted in compensatory increase of the other. MUC5B protected mice from increased bacterial load with neutrophil infiltration in airways, but MUC5B and MUC5AC were similarly important to prevent eosinophilia in lungs and distal compartments. Airway inflammation correlated with epithelial shedding, aberrant expression of epithelial integrity genes, increased epithelial permeability, and altered alarmins along with activation of innate lymphoid cells upon mucin disruption. Finally, IL-33 airway challenge increased Muc5b and Muc5ac where both mucins were required for normal granulocyte recruitment to lungs. CONCLUSION: MUC5B and MUC5AC play nonredundant yet complementary roles in maintaining airway immune homeostasis and regulating inflammation. Loss or imbalance of either mucin disrupts normal epithelial responses and compromises barrier integrity, potentially driving downstream changes in immune cell composition locally and systemically. It highlights an underappreciated immunomodulatory function of airway mucus which sheds new light on its role in asthma and COPD.