MUC5B regulates goblet cell differentiation and reduces inflammation in a murine COPD model

Abstract Background Airway mucus hypersecretion is one of the important pathological features of chronic obstructive pulmonary disease (COPD). MUC5B is the main mucin expressed in the airways of COPD patients and has been indicated to play an important role in airway defense. However, the specific biological function of MUC5B in COPD and the possible mechanism are not clear. Methods We established a COPD model with 24-week-old MUC5B−/− mice exposed to cigarette smoke and tested our hypothesis through lung function tests, HE and PAS staining, immunohistochemistry (IHC), western blot, q-PCR and ELISA. Results Compared with MUC5B+/+ mice, MUC5B−/− mice had worse general condition and lung function, increased inflammatory infiltration, reduced goblet cell differentiation as indicated by decreased PAS staining (PAS grade: 1.8 ± 0.24 vs. 0.6 ± 0.16), reduced MUC5AC expression (ELISA: 0.30 ± 0.01 vs. 0.17 ± 0.01 mg/ml, q-PCR: 9.4 ± 1.7 vs. 4.1 ± 0.1 fold, IHC score: 3.1 ± 0.9 vs. 1.6 ± 0.7), increased macrophage secretion of inflammatory factors (TNF-α and IL-6) and expression of downstream pathway factors (ERK1/2 and NF-κB), decreased expression of SPDEF and STAT6, and increased expression of FOXA2. Conclusion The protective effect of MUC5B in the development of COPD was mediated by the promotion of goblet cell differentiation and the inhibition of inflammation. The role of MUC5B in regulating inflammation was related to macrophage function, and goblet cell differentiation was promoted by the induced expression of STAT6 and SPDEF. This study describes a mechanism of mucus hypersecretion and identifies MUC5B as a new target for the treatment of mucus hypersecretion.