title: Polysialic acid blocks mononuclear phagocyte reactivity, inhibits complement activation, and protects from vascular damage in the retina.
abstract: Age-related macular degeneration (AMD) is a major cause of blindness in the elderly population. Its pathophysiology is linked to reactive oxygen species (ROS) and activation of the complement system. Sialic acid polymers prevent ROS production of human mononuclear phagocytes via the inhibitory sialic acid-binding immunoglobulin-like lectin-11 (SIGLEC11) receptor. Here, we show that low-dose intravitreal injection of low molecular weight polysialic acid with average degree of polymerization 20 (polySia avDP20) in humanized transgenic mice expressing SIGLEC11 on mononuclear phagocytes reduced their reactivity and vascular leakage induced by laser coagulation. Furthermore, polySia avDP20 prevented deposition of the membrane attack complex in both SIGLEC11 transgenic and wild-type animals. In vitro, polySia avDP20 showed two independent, but synergistic effects on the innate immune system. First, polySia avDP20 prevented tumor necrosis factor-α, vascular endothelial growth factor A, and superoxide production by SIGLEC11-positive phagocytes. Second, polySia avDP20 directly interfered with complement activation. Our data provide evidence that polySia avDP20 ameliorates laser-induced damage in the retina and thus is a promising candidate to prevent AMD-related inflammation and angiogenesis.
authors.affiliation: Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Cologne, Germany.|Therapeutic Research Group Ophthalmology, Bayer Pharma AG, Wuppertal, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Karlstetter
authors.affiliation: Institute of Reconstructive Neurobiology, University Hospital Bonn, University of Bonn, Bonn, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Kopatz
authors.affiliation: Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Cologne, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Aslanidis
authors.affiliation: Institute of Reconstructive Neurobiology, University Hospital Bonn, University of Bonn, Bonn, Germany.
authors.forename: Anahita
authors.initials: A
authors.lastname: Shahraz
authors.affiliation: Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Cologne, Germany.
authors.forename: Albert
authors.initials: A
authors.lastname: Caramoy
authors.affiliation: Institute of Reconstructive Neurobiology, University Hospital Bonn, University of Bonn, Bonn, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Linnartz-Gerlach
authors.affiliation: Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany.
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Cologne, Germany.
authors.forename: Anika
authors.initials: A
authors.lastname: Lückoff
authors.affiliation: Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Cologne, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Fauser
authors.affiliation: Institute of Reconstructive Neurobiology, University Hospital Bonn, University of Bonn, Bonn, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Düker
authors.affiliation: Institute of Reconstructive Neurobiology, University Hospital Bonn, University of Bonn, Bonn, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Claude
authors.affiliation: Institute of Reconstructive Neurobiology, University Hospital Bonn, University of Bonn, Bonn, Germany.
authors.forename: Yiner
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Institute of Reconstructive Neurobiology, University Hospital Bonn, University of Bonn, Bonn, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Ackermann
authors.affiliation: Institute of Molecular Medicine, University Hospital Bonn, University of Bonn, Bonn, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Schmidt
authors.affiliation: Institute of Molecular Medicine, University Hospital Bonn, University of Bonn, Bonn, Germany.|Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Veit
authors.initials: V
authors.lastname: Hornung
authors.affiliation: Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Skerka
authors.affiliation: Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Cologne, Germany thomas.langmann@uk-koeln.de hneuman1@uni-bonn.de.
authors.forename: Thomas
authors.identifier: 0000-0001-6826-529X
authors.initials: T
authors.lastname: Langmann
authors.affiliation: Institute of Reconstructive Neurobiology, University Hospital Bonn, University of Bonn, Bonn, Germany thomas.langmann@uk-koeln.de hneuman1@uni-bonn.de.
authors.forename: Harald
authors.identifier: 0000-0002-5071-5202
authors.initials: H
authors.lastname: Neumann
mesh_terms: D000818:Animals; D020256:Choroidal Neovascularization / Q000517:prevention & control*; D003167:Complement Activation; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage*; D007834:Lasers; D037102:Lectins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D016513:Mice, SCID; D008822:Mice, Transgenic; D010586:Phagocytes / Q000187:drug effects* / Q000276:immunology*; D012160:Retina / Q000293:injuries*; D012794:Sialic Acids / Q000008:administration & dosage*
chemical_list: D007155:Immunologic Factors; D037102:Lectins; D008565:Membrane Proteins; C464442:SIGLEC11 protein, human; D012794:Sialic Acids; C021319:polysialic acid
keywords: 
  SIGLEC
  ; age‐related macular degeneration; complement; microglia; polysialic acid