Different Munc18 proteins mediate baseline and stimulated airway mucin secretion

Area of Science:

• Cell Biology
• Respiratory Medicine

Background:

• Airway mucin secretion is vital for clearing inhaled substances but contributes to diseases like asthma and cystic fibrosis.
• Exocytosis, the process of secretion, relies on Munc18 scaffolding proteins, with airway secretory cells expressing three isoforms: Munc18a, Munc18b, and Munc18c.

Purpose of the Study:

• To investigate the specific roles of Munc18a, Munc18b, and Munc18c in airway mucin secretion.
• To evaluate the therapeutic potential of targeting Munc18b in models of allergic asthma and cystic fibrosis.

Main Methods:

• Utilized conditional airway epithelial cell-specific Munc18-deletant mouse models.
• Assessed mucin secretion under baseline and stimulated conditions.
• Examined airway mucus occlusion, airflow resistance, emphysema, lung structure, particle clearance, inflammation, and bacterial infection in disease models.

Main Results:

• Munc18a primarily regulates baseline mucin secretion.
• Munc18b is the major regulator of stimulated mucin secretion.
• Munc18c plays no role in mucin secretion.
• Munc18b deletion significantly reduced airway mucus occlusion and airflow resistance in an asthma model.
• Munc18b deletion reduced mucus occlusion and emphysema in a cystic fibrosis model.
• Munc18b deficiency did not impair lung structure, particle clearance, inflammation, or bacterial infection.

Conclusions:

• Regulated exocytosis in polarized airway epithelial cells may involve multiple apical exocytic machinery.
• Targeting Munc18b in airway epithelium offers a therapeutic strategy to mitigate pathological mucin secretion in diseases like asthma and cystic fibrosis while preserving protective functions.