Muc5b Is Required for Airway Defense
By Michelle G. Roy, A. Livraghi-Butrico, Ashley A. Fletcher, Melissa M. McElwee, S. Evans, R. Boerner, Samantha N. Alexander, Lindsey K. Bellinghausen, Alfred S. Song, Youlia M. Petrova and 33 more. Nature, 2013
703 citations recorded by the source corpus.
Respiratory surfaces are exposed to billions of particulates and pathogens daily. A protective mucus barrier traps and eliminates them through mucociliary clearance (MCC). However, excessive mucus contributes to transient respiratory infections and to the pathogenesis of numerous respiratory diseases. MUC5AC and MUC5B are evolutionarily conserved genes that encode structurally related mucin glycoproteins, the principal macromolecules in airway mucus. Genetic variants are linked to diverse lung diseases, but specific roles for MUC5AC and MUC5B in MCC, and the lasting effects of their inhibition, are unknown. Here we show that mouse Muc5b (but not Muc5ac) is required for MCC, for controlling infections in the airways and middle ear, and for maintaining immune homeostasis in mouse lungs, whereas Muc5ac is dispensable. 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 normally. Apoptotic macrophages accumulated, phagocytosis was impaired, and interleukin-23 (IL-23) production was reduced in Muc5b−/− mice. By contrast, in mice that transgenically overexpress Muc5b, 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 sputum. However, in many patients, MUC5B production at airway surfaces decreases by as much as 90%. 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.
Subfields: Physiology, Pulmonary and Respiratory Medicine
View Paper: https://www.semanticscholar.org/paper/4cc52d021f16c71b3896682b3ba1c36008525960
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In Pulmonary and Respiratory Medicine
Citations in the corpus
- The microbiota of the respiratory tract: gatekeeper to respiratory health (2017, background): “In addition, the glycoproteins in the mucus accommodate resident microorganisms and prevent infection 132 , as evidenced by the decrease in antibacterial cytokines and the presence of phagocytosis-impaired macrophages in the lungs of mucin-deficient mice 133 .”
- Biological roles of glycans (2016, background): “Disruption of this layer by genetically altering mucin backbones, O-linked glycosyltransferases (or key chaperones like Cosmc) can have very serious consequences, including inflammation and carcinogenesis associated with microbial invasion (453) (454) (455) (456) .”