MUC1 is a membrane-bound mucin expressed on the apical surfaces of most mucosal epithelial cells. In normal lung epithelia, MUC1 is a binding site for Pseudomonas aeruginosa, an opportunistic human pathogen of great clinical importance. It has now been established that MUC1 also serves an anti-inflammatory role in the airways that is initiated late in the course of a bacterial infection and is mediated through inhibition of Toll-like receptor (TLR) signaling. MUC1 expression was initially shown to interfere with TLR5 signaling in response to P. aeruginosa flagellin, but has since been extended to other TLRs. These new findings point to an immunomodulatory role for MUC1 during P. aeruginosa lung infection, particularly during the resolution phase of inflammation. This review briefly summarizes the recent characterization of MUC1’s anti-inflammatory properties in both the respiratory tract and extrapulmonary tissues.

MUC1 (MUC in human; Muc in animals) is a transmembrane mucin glycoprotein expressed in mucosal epithelial cells and hematopoietic cells. MUC1 is involved in the resolution of inflammation during airway Pseudomonas aeruginosa (Pa) infection by suppressing Toll-like receptor signaling in airway epithelial cells. Although alveolar macrophages are recognized as critical mediators of cell-mediated immunity against microorganisms inhaled into the airways, the role of MUC1 in regulating their response is unknown. The aims of this study were to determine whether macrophages express MUC1, and, if so, whether MUC1 expression might be associated with macrophage M0/M1/M2 differentiation or phagocytic activity. Human and mouse MUC1/Muc1 expression was drastically up-regulated in classically activated (M1) macrophages compared with nonactivated (M0) and alternatively activated (M2) macrophages. M1 polarization and Pa stimulation each increased MUC1 ectodomain shedding from the macrophage surface in a TNF-α–converting enzyme–dependent manner. MUC1/Muc1 deficiency in M0 macrophages increased adhesion and phagocytosis of Pa and Escherichia coli compared with MUC1/Muc1–expressing cells, and attenuation of phagocytosis by MUC1 was augmented after polarization into M1 macrophages compared with M0 macrophages. Finally, MUC1/Muc1 deficiency in macrophages increased reactive oxygen species production and TNF-α release in response to Pa compared with MUC1/Muc1–sufficient cells. These results indicate that MUC1/Muc1 expression by macrophages is predominantly in the M1 subtype, and that MUC1/Muc1 expression in these cells decreases their phagocytic activity in an antiinflammatory manner.

Airway mucins, the major component of airway mucus or apical surface fluid that covers the entire surface of the airways, have been shown to possess multi-factorial functions that are necessary for first line defense, the major function of airway mucus. In this mini-review, I will provide some evidence, both theoretical and experimental, that the multi-factorial functions of airway mucins are most likely due to various bioactive proteins that are tightly associated with mucins. Thus, the first line defense of airway mucus requires both the mucociliary clearance and the activity of various bioactive proteins tightly associated with mucins, which depend on the quality and quantity of airway mucins.