title: Soluble polysialylated NCAM: a novel player of the innate immune system in the lung.
abstract: Posttranslational modification of the neural cell adhesion molecule (NCAM) by polysialic acid (polySia) is well studied in the nervous system and described as a dynamic modulator of plastic processes like precursor cell migration, axon fasciculation, and synaptic plasticity. Here, we describe a novel function of polysialylated NCAM (polySia-NCAM) in innate immunity of the lung. In mature lung tissue of healthy donors, polySia was exclusively attached to the transmembrane isoform NCAM-140 and located to intracellular compartments of epithelial cells. In patients with chronic obstructive pulmonary disease, however, increased polySia levels and processing of the NCAM carrier were observed. Processing of polysialylated NCAM was reproduced in a mouse model by bleomycin administration leading to an activation of the inflammasome and secretion of interleukin (IL)-1β. As shown in a cell culture model, polySia-NCAM-140 was kept in the late trans-Golgi apparatus of lung epithelial cells and stimulation by IL-1β or lipopolysaccharide induced metalloprotease-mediated ectodomain shedding, resulting in the secretion of soluble polySia-NCAM. Interestingly, polySia chains of secreted NCAM neutralized the cytotoxic activity of extracellular histones as well as DNA/histone-network-containing "neutrophil extracellular traps", which are formed during invasion of microorganisms. Thus, shedding of polySia-NCAM by lung epithelial cells may provide a host-protective mechanism to reduce tissue damage during inflammatory processes.
authors.affiliation: Institute of Biochemistry, Justus-Liebig-University, Giessen, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Ulm
authors.forename: Mona
authors.initials: M
authors.lastname: Saffarzadeh
authors.forename: Poornima
authors.initials: P
authors.lastname: Mahavadi
authors.forename: Sandra
authors.initials: S
authors.lastname: Müller
authors.forename: Gerlinde
authors.initials: G
authors.lastname: Prem
authors.forename: Farhan
authors.initials: F
authors.lastname: Saboor
authors.forename: Peter
authors.initials: P
authors.lastname: Simon
authors.forename: Ralf
authors.initials: R
authors.lastname: Middendorff
authors.forename: Hildegard
authors.initials: H
authors.lastname: Geyer
authors.forename: Ingrid
authors.initials: I
authors.lastname: Henneke
authors.forename: Nils
authors.initials: N
authors.lastname: Bayer
authors.forename: Susanne
authors.initials: S
authors.lastname: Rinné
authors.forename: Thomas
authors.initials: T
authors.lastname: Lütteke
authors.forename: Eva
authors.initials: E
authors.lastname: Böttcher-Friebertshäuser
authors.forename: Rita
authors.initials: R
authors.lastname: Gerardy-Schahn
authors.forename: David
authors.initials: D
authors.lastname: Schwarzer
authors.forename: Martina
authors.initials: M
authors.lastname: Mühlenhoff
authors.forename: Klaus T
authors.initials: KT
authors.lastname: Preissner
authors.forename: Andreas
authors.initials: A
authors.lastname: Günther
authors.forename: Rudolf
authors.initials: R
authors.lastname: Geyer
authors.forename: Sebastian P
authors.initials: SP
authors.lastname: Galuska
mesh_terms: D000328:Adult; D000818:Animals; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000276:immunology; D005260:Female; D006657:Histones / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D058847:Inflammasomes / Q000276:immunology; D053583:Interleukin-1beta / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D008168:Lung / Q000276:immunology*; D008297:Male; D008565:Membrane Proteins / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D008958:Models, Molecular; D019006:Neural Cell Adhesion Molecules / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology; D020033:Protein Isoforms; D011499:Protein Processing, Post-Translational; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology; D012794:Sialic Acids / Q000276:immunology*; D015854:Up-Regulation / Q000276:immunology; D021601:trans-Golgi Network / Q000276:immunology
chemical_list: D006657:Histones; D058847:Inflammasomes; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D019006:Neural Cell Adhesion Molecules; D020033:Protein Isoforms; D012794:Sialic Acids; C021319:polysialic acid