title: 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-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.
authors.affiliation: 1 Department of Otolaryngology, University of Arizona College of Medicine, Tucson, Arizona.|2 Center for Inflammation, Translational and Clinical Lung Research, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Kato
authors.affiliation: 2 Center for Inflammation, Translational and Clinical Lung Research, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Reina
authors.initials: R
authors.lastname: Uchino
authors.affiliation: 3 Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Erik P
authors.initials: EP
authors.lastname: Lillehoj
authors.affiliation: 4 Department of Medicine, University of Arizona College of Medicine, Tucson, Arizona; and.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Knox
authors.affiliation: 5 Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico(Received in original form May 28, 2015 and in final form September 15, 2015).
authors.forename: Yong
authors.initials: Y
authors.lastname: Lin
authors.affiliation: 1 Department of Otolaryngology, University of Arizona College of Medicine, Tucson, Arizona.|2 Center for Inflammation, Translational and Clinical Lung Research, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: K Chul
authors.initials: KC
authors.lastname: Kim
mesh_terms: D000818:Animals; D001422:Bacterial Adhesion; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018396:Mucin-1 / Q000502:physiology*; D010587:Phagocytosis / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D018396:Mucin-1; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha
keywords: MUC1 mucin; Pseudomonas aeruginosa; inflammation; macrophage; phagocytosis