Regulation of Microbial Populations and Immune Functions by Muc5b

Abstract

The MUC5AC and MUC5B genes encode mucin glycoproteins that are structurally similar and are the principal macromolecules in airway mucus. In spite of its beneficial function, mucus overproduction, hypersecretion, and accumulation are associated with chronic lung diseases and have emerged as attractive therapeutic targets. However, specific roles of MUC5AC and MUC5B in mucociliary clearance (MCC), and the lasting effects of their inhibition, are unknown. Here, using two mouse lines lacking Muc5ac and Muc5b, we show that whereas Muc5ac is dispensable at baseline, Muc5b is required for normal respiratory function, MCC, and survival. Strikingly, in addition to acutely controlling particle elimination, Muc5b is also crucial for maintaining homeostatic microbial composition and innate immune responsiveness. We found that Muc5b (but not Muc5ac) deficiency caused a significant increase in culturable bacteria in the lungs. This was marked by a significant shift in the diversity of cultured organisms—notably characterized by the acquisition of Staphylococcus aureus. Thus, Muc5b is essential for controlling homeostatic and pathological microbial populations in the lungs. Because MUC5B is reduced in asthma and chronic obstructive pulmonary disease, Muc5b-deficient mice provide a useful basis for establishing the nature of host–environment interactions in regulating microbiota composition. Recent work from our laboratory focuses on how Muc5b expression controls microbiome composition and function at baseline and in response to chronic inflammation. At baseline, loss of Muc5b is compensated for by macrophage-mediated clearance and innate type 17 immune responses. However, chronic loss of Muc5b causes a 50% reduction in macrophage phagocytosis and a greater than 95% reduction in IL-23. These studies identify mechanisms by which Muc5b regulates barrier and immune functions in the lungs, and they demonstrate that Muc5ac and Muc5b serve distinct and specific roles in the airways. Our results also provide a framework for designing targeted therapies to reduce mucus hypersecretion and enhance MCC in chronic lung diseases.