title: Polysialylation and lipopolysaccharide-induced shedding of E-selectin ligand-1 and neuropilin-2 by microglia and THP-1 macrophages.
abstract: Microglia are tissue macrophages and mediators of innate immune responses in the brain. The protein-modifying glycan polysialic acid (polySia) is implicated in modulating microglia activity. Cultured murine microglia maintain a pool of Golgi-confined polySia, which is depleted in response to lipopolysaccharide (LPS)-induced activation. Polysialylated neuropilin-2 (polySia-NRP2) contributes to this pool but further polySia protein carriers have remained elusive. Here, we use organotypic brain slice cultures to demonstrate that injury-induced activation of microglia initiates Golgi-confined polySia expression in situ. An unbiased glycoproteomic approach with stem cell-derived microglia identifies E-selectin ligand-1 (ESL-1) as a novel polySia acceptor. Together with polySia-NRP2, polySia-ESL-1 is also detected in primary cultured microglia, in brain slice cultures and in phorbol ester-induced THP-1 macrophages. Induction of stem cell-derived microglia, activated microglia in brain slice cultures and THP-1 macrophages by LPS, but not interleukin-4, causes polySia depletion and, as shown for stem cell-derived microglia, a metalloproteinase-dependent release of polySia-ESL-1 and polySia-NRP2. Moreover, soluble polySia attenuates LPS-induced production of nitric oxide and proinflammatory cytokines. Thus, shedding of polySia-ESL-1 and polySia-NRP2 after LPS-induced activation of microglia and THP-1 macrophages may constitute a mechanism for negative feedback regulation. GLIA 2016 GLIA 2016;64:1314-1330.
authors.affiliation: Institute for Cellular Chemistry, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, Hannover, Germany.|Center for Systems Neuroscience (ZSN), Hannover, Bünteweg 2, 30559, Hannover, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Werneburg
authors.affiliation: Institute for Cellular Chemistry, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, Hannover, Germany.
authors.forename: Falk F R
authors.initials: FF
authors.lastname: Buettner
authors.affiliation: Institute for Cellular Chemistry, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, Hannover, Germany.
authors.forename: Larissa
authors.initials: L
authors.lastname: Erben
authors.affiliation: Institute of Reconstructive Neurobiology, University of Bonn, Sigmund-Freud-Straße 25, 53127, Bonn, Germany.
authors.forename: Mona
authors.initials: M
authors.lastname: Mathews
authors.affiliation: Institute of Reconstructive Neurobiology, University of Bonn, Sigmund-Freud-Straße 25, 53127, Bonn, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Neumann
authors.affiliation: Institute for Cellular Chemistry, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, Hannover, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Mühlenhoff
authors.affiliation: Institute for Cellular Chemistry, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, Hannover, Germany.|Center for Systems Neuroscience (ZSN), Hannover, Bünteweg 2, 30559, Hannover, Germany.
authors.forename: Herbert
authors.initials: H
authors.lastname: Hildebrandt
mesh_terms: D000818:Animals; D001921:Brain / Q000276:immunology / Q000473:pathology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004926:Escherichia coli; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity*; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D018345:Mice, Knockout; D017628:Microglia / Q000276:immunology* / Q000473:pathology; D019006:Neural Cell Adhesion Molecules / Q000172:deficiency / Q000235:genetics; D058953:Neural Stem Cells / Q000276:immunology / Q000473:pathology; D039943:Neuropilin-2 / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D011134:Polysaccharides / Q000633:toxicity*; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D012795:Sialoglycoproteins / Q000378:metabolism; D012799:Sialyltransferases / Q000172:deficiency / Q000235:genetics; D000074084:THP-1 Cells / Q000276:immunology* / Q000473:pathology; D046509:Tissue Culture Techniques
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D019006:Neural Cell Adhesion Molecules; D039943:Neuropilin-2; D011134:Polysaccharides; D017468:Receptors, Fibroblast Growth Factor; D012795:Sialoglycoproteins; C086711:cysteine-rich fibroblast growth factor receptor; D009569:Nitric Oxide; C014420:colominic acid; D012799:Sialyltransferases; C525848:ST8SiaIV protein, mouse
keywords: GLG1; PSA-NCAM; immunomodulation; microglia activation; protein glycosylation