Role of epithelial mucins during airway infection

Abstract

Airway surface fluid contains two layers of mucins consisting mainly of 5 different mucin gene products. While the outer layer contains two gel-forming mucins (MUC5AC and MUC5B) that are tightly associated with various biologically active, defensive molecules, the inner layer contains three membrane-tethered mucins (MUC1, MUC4 and MUC16) shed from the apical cell surface. During airway infection, all of these mucins serve as a major protective barrier against pathogens. MUC1 mucin produced by virtually all the surface columnar epithelial cells in the respiratory tract as well as Type II pneumocytes in the alveoli plays an additional, perhaps more critical role during respiratory infection by controlling the resolution of inflammation that is essential to prevent the development of inflammatory lung disease.

Fig. 1. Anti-inflammatory role of MUC1 during airway infection

(Step 1) During the early stage of infection by P. aeruginosa (PA), bacterial PAMPs (e.g. flagellin) activate TLRs and NF-κB on epithelial cells and macrophages (M). (2) Activation of NF-κB leads to increased expression of TNF-α and of IL-8, which are subsequently secreted. (3) IL-8 recruits neutrophils (N) across the epithelial barrier that release NE into the lumen of the airways. (4) NE and TNF-α up-regulate MUC1 gene expression resulting in increased expression of MUC1 mucin at the apical surface of lung epithelial cells. (5) During the late stage of infection, tyrosine phosphorylation of MUC1 CT domain leads to inhibition of TLR signaling and (6) down-regulation of inflammation. (Fom Kim and Lillejoj [36])