Membrane-Tethered MUC1 Mucin Counter-Regulates the Phagocytic Activity of Macrophages

Abstract

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.

Transmembrane Mucins: Signaling Receptors at the Intersection of Inflammation and Cancer

“…Limited data are available on the function of transmembrane mucins in these cells, but it seems likely that, as in epithelial cells, they have immunomodulatory and signaling functions. In line with its anti-inflammatory effects in healthy epithelial cells, MUC1 dampens phagocytosis by macrophages [101] and decreases secretion of TNF-α and IFN-γ after stimulation with LPS or flagellin in dendritic cells (DCs). The importance of MUC1-mediated immune dampening is illustrated by the continuous activation of DCs after knocking out MUC1 [102].…”

Pseudomonas aeruginosa increases MUC1 expression in macrophages through the TLR4-p38 pathway

“…Our previous in vitro studies revealed that the paracrine TNF-TNFR1-ERK1/2-Sp1 signaling pathway is responsible for MUC1 up-regulation in lung epithelial cells [17–20] . We recently reported that MUC1 expression by both human and mouse AMs was substantially up-regulated in Pa-stimulated or classically activated (M1) macrophages compared with unactivated (M0) and alternatively activated (M2) macrophages [21] . Further, MUC1 expression by macrophages was associated with attenuated innate immune responses such as phagocytic activity and cytokine production [21] .…”

“…We recently reported that MUC1 expression by both human and mouse AMs was substantially up-regulated in Pa-stimulated or classically activated (M1) macrophages compared with unactivated (M0) and alternatively activated (M2) macrophages [21] . Further, MUC1 expression by macrophages was associated with attenuated innate immune responses such as phagocytic activity and cytokine production [21] . These results support a growing body of evidence suggesting a pivotal, immunomodulatory function of MUC1 in a subpopulation of macrophages during Pa lung infection.…”

Mucin 1 is a novel glycoprotein involved in host defense against invasive pneumococcal disease

“…10 One of these receptors involved in host defense, is Mucin 1 (MUC1) that is a cell membrane-associated glycoprotein expressed on the majority of epithelial cells including the respiratory tract and the middle ear, which are target sites for pneumococcal infection, and also in immune cells such as B cells, T cells, macrophages and dendritic cells. 11,12 In this issue of Virulence, Dhar and colleagues demonstrate the protective role of MUC1 against invasive pneumococcal disease. 13 Using wild-type and Muc1 ¡/¡ mice, the authors investigated the impact of MUC1 deficiency in pneumococcal pathogenesis.…”

“…15 In the case of Gram-negative microorganisms such as Pseudomonas aeruginosa and Escherichia coli, inhibition of MUC1 expression enhances the phagocytic activity of human macrophages and the explanation for this phenotype is because MUC1 may attenuate bacterial adhesion to macrophages. 12 One possible reason for this discrepancy might be due to the presence of LPS in Gram-negative bacteria although further research is needed to address this possibility.…”