Background: Pseudomonas aeruginosa flagellin binds to the membrane-tethered mucin, MUC1. Results: Flagellin drives NEU1 to desialylate MUC1, thereby increasing its adhesiveness for Pseudomonas aeruginosa and its shedding. Conclusion: P. aeruginosa hijacks host NEU1 through its flagellin. Significance: P. aeruginosa mobilizes NEU1 to enhance its pathogenicity, but the host retaliates by releasing MUC1 as a hyperadhesive decoy receptor.

Helicobacter pylori infection of the gastric mucosa causes an active-chronic inflammation that is strongly linked to the development of duodenal and gastric ulcers and stomach cancer.

MUC1 is a transmembrane glycoprotein expressed on the apical surface of airway epithelial cells and plays an anti-inflammatory role during airway bacterial infection. In this study, we determined whether the anti-inflammatory effect of MUC1 is also operative during the respiratory syncytial virus (RSV) infection. The lung epithelial cell line A549 was treated with RSV, and the production of TNFalpha and the levels of MUC1 protein were monitored temporally during the course of infection by ELISA and Western blot analysis. Small inhibitory RNA (siRNA) transfection was utilized to assess the role of MUC1 in regulating RSV-mediated inflammatory responses by lung epithelial cells. Our results revealed that: 1) following RSV infection, an increase in MUC1 level was preceded by an increase in TNFalpha production and completely inhibited by soluble TNF receptor (TNFR); and 2) knockdown of MUC1 using MUC1 siRNA resulted in a greater increase in TNFalpha level following RSV infection compared with control siRNA treatment. We conclude that the RSV-induced increase in the TNFalpha levels upregulates MUC1 through its interaction with TNFR, which in turn suppresses further increase in TNFalpha by RSV, thus forming a negative feedback loop in the control of RSV-induced inflammation. This is the first demonstration showing that MUC1 can suppress the virus-induced inflammatory responses.

MUC1 is a membrane-tethered mucin glycoprotein expressed on the apical surface of mucosal epithelial cells. Previous in vivo and in vitro studies established that MUC1 counter-regulates airway inflammation by suppressing TLR signaling. In this report, we elucidate the mechanism by which MUC1 inhibits TLR5 signaling. Overexpression of MUC1 in human embryonic kidney HEK293 (293) cells dramatically reduced Pseudomonas aeruginosa (Pa)-stimulated IL-8 expression, and decreased the activation of NF-κB and MAPK compared with MUC1 non-expressing cells. Overexpression of MUC1 in 293 cells, however, did not affect NF-κB or MAKP activation in response to TNF-α. Overexpression of MyD88 abrogated the ability of MUC1 to inhibit NF-κB activation, and MUC1 overexpression inhibited flagellin-induced association of TLR5/MyD88, compared with controls. The MUC1 cytoplasmic tail (MUC1 CT) associated with TLR5 in all cells tested, including 293T cells, human lung adenocarcinoma cell line A549 cells, and human and mouse primary airway epithelial cells. Activation of EGFR tyrosine kinase with TGF-α induced phosphorylation of the MUC1 CT at the Y46 EKV sequence and increased association of MUC1/TLR5. Finally, in vivo experiments demonstrated increased immunofluorescence co-localization of Muc1/TLR5 and Muc1/phosphotyrosine staining patterns in mouse airway epithelium and increased Muc1 tyrosine phosphorylation in mouse lung homogenates following Pa infection. In conclusion, EGFR tyrosine phosphorylates MUC1, leading to an increase in its association with TLR5, thereby competitively and reversibly inhibiting recruitment of MyD88 to TLR5 and downstream signaling events. This unique ability of MUC1 to control TLR5 signaling suggests its potential role in the pathogenesis of chronic inflammatory lung diseases.

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-a-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-a 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.