Muc5b is required for airway defence

Abstract

Respiratory surfaces are exposed to billions of particulates and pathogens daily. A protective mucus barrier traps and eliminates them via mucociliary clearance (MCC)1,2. However, excessive mucus contributes to transient respiratory infections and to the pathogenesis of numerous respiratory diseases1. MUC5AC and MUC5B are evolutionarily conserved genes that encode structurally related mucin glycoproteins, the principal macromolecules in airway mucus1,3. Genetic variants are linked to diverse lung diseases4-6, but specific roles for MUC5AC and MUC5B in MCC, and the lasting effects of their inhibition, are unknown. Here we show that Muc5b (but not Muc5ac) is required for MCC, for controlling infections in the airways and middle ear, and for maintaining immune homeostasis in the lungs. Muc5b deficiency caused materials to accumulate in upper and lower airways. This defect led to chronic infection by multiple bacterial species, including Staphylococcus aureus, and to inflammation that failed to resolve normally7. Apoptotic macrophages accumulated, phagocytosis was impaired, and IL-23 production was reduced inMuc5b−/− mice. By contrast, in Muc5b transgenic (Tg) mice, macrophage functions improved. Existing dogma defines mucous phenotypes in asthma and chronic obstructive pulmonary disease (COPD) as driven by increased MUC5AC, with MUC5B levels either unaffected or increased in expectorated sputum1,8. However, in many patients, MUC5B production at airway surfaces decreases by as much as 90%9-11. By distinguishing a specific role for Muc5b in MCC, and by determining its impact on bacterial infections and inflammation in mice, our results provide a refined framework for designing targeted therapies to control mucin secretion and restore MCC.

Oxidative and endoplasmic reticulum stress in respiratory disease

“…This airway mucus is composed mainly of mucin glycoproteins and water, and provides a matrix for a wide variety of antimicrobial molecules including antibodies, defensins, protegrins, collectins, cathelicidins, lysozyme, histatins and nitric oxide21, 22, 23. When the mucus barrier has increased viscosity making it resistant to mucociliary clearance, or when the barrier is deficient or depleted, the risk of opportunistic microbial infection is increased 24. Mucins, primarily MUC5B, are tonically secreted by the nonciliated airway epithelial surface cells, known as club cells in the small airway, and can be released in large amounts in response to inhaled material by submucosal gland mucous cells, which contain large numbers of mucin granules ready for stimulated secretion 22…”

Gel-forming mucins form distinct morphologic structures in airways

“…In mouse lungs, MUC5B and MUC5AC are expressed primarily in club cells (1,10). Mice with a disrupted Muc5b gene accumulated mucus in the upper airway, whereas mice with a disrupted Muc5ac gene lacked apparent respiratory abnormalities (10). Together, these results suggest that MUC5B and MUC5AC may have different functions.…”

“…In human airways, MUC5B is produced in submucosal glands and goblet cells, and MUC5AC is produced in goblet cells (1,4,5,9). In mouse lungs, MUC5B and MUC5AC are expressed primarily in club cells (1,10). Mice with a disrupted Muc5b gene accumulated mucus in the upper airway, whereas mice with a disrupted Muc5ac gene lacked apparent respiratory abnormalities (10).…”

MUC5B mucin production is upregulated by fibronectin and laminin in human lung epithelial cells via the integrin and ERK dependent pathway

“…A previous study on mice demonstrated that MUC5B mucin deficiency is associated with MCC dysfunction and causes difficulty in biodefense of the airway. 10) However, overproduction of MUC5B or MUC5AC mucin causes narrowing of the airway. A primary symptom of patients with COPD and asthma is hypersecretion of airway mucus with hyperplasia and it causes airflow limitation.…”

“…It shows a small increase in the airway of patients with respiratory diseases, but it is required for biodefense of the airway, with a lack of MUC5B inducing inefficient MCC. [8][9][10] MUC5AC production is regulated in various ways, such as by inflammatory cytokines (interleukin-1β, tumor necrosis factor-α), cell-cell adhesion molecules, and EGF receptors. 11,12) However, little is known about the regulation of MUC5B production.…”