title: Metabolic sialic acid blockade lowers the activation threshold of moDCs for TLR stimulation.
abstract: Sialic acid sugars cover the surface of dendritic cells (DCs) and have been suggested to impact several aspects of DC biology. Research into the role of sialic acids in DCs, however, is complicated by the limited number of tools available to modulate sialic acid expression. Here we report on a synthetic, fluorinated sialic acid mimetic, Ac53FaxNeu5Ac, which potently blocks sialic acid expression in human monocyte-derived DCs (moDCs). Sialic acid blockade enhanced the responsiveness of moDCs to Toll-like receptor (TLR) stimulation as measured by increased maturation marker expression and cytokine production. Consequently, the T-cell activation capacity of Ac53FaxNeu5Ac-treated moDCs was strongly increased. In addition to sialic acids, moDCs also expressed the sialic acid-binding immunoglobulin-like lectins (Siglecs) -3, -5, -7, -9 and -10, immune inhibitory receptors recognizing these sialic acids. Treatment with Ac53FaxNeu5Ac abrogated putative cis and trans interactions between sialic acids and Siglec-7/-9. Together, these data indicate that sialic acids limit the activation of moDCs via the TLR pathway, potentially by interacting with Siglec-7 or Siglec-9. Metabolic sialic acid blockade with Ac53FaxNeu5Ac could therefore potentially be used to generate more potent DC-based vaccines for induction of robust anti-viral or anti-tumor immune responses.
authors.affiliation: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 28, 6525 GA Nijmegen, The Netherlands.
authors.forename: Christian
authors.initials: C
authors.lastname: Büll
authors.affiliation: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 28, 6525 GA Nijmegen, The Netherlands.
authors.forename: Estel
authors.initials: E
authors.lastname: Collado-Camps
authors.affiliation: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 28, 6525 GA Nijmegen, The Netherlands.
authors.forename: Esther D
authors.initials: ED
authors.lastname: Kers-Rebel
authors.affiliation: Cluster for Molecular Chemistry, Institute for Molecules and Materials, Radboud University Nijmegen, Nijmegen, The Netherlands.
authors.forename: Torben
authors.initials: T
authors.lastname: Heise
authors.affiliation: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 28, 6525 GA Nijmegen, The Netherlands.
authors.forename: Jonas N
authors.initials: JN
authors.lastname: Søndergaard
authors.affiliation: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 28, 6525 GA Nijmegen, The Netherlands.
authors.forename: Martijn H
authors.initials: MH
authors.lastname: den Brok
authors.affiliation: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 28, 6525 GA Nijmegen, The Netherlands.
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Schulte
authors.affiliation: Cluster for Molecular Chemistry, Institute for Molecules and Materials, Radboud University Nijmegen, Nijmegen, The Netherlands.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Boltje
authors.affiliation: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 28, 6525 GA Nijmegen, The Netherlands.
authors.forename: Gosse J
authors.initials: GJ
authors.lastname: Adema
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D000943:Antigens, Differentiation / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D032701:Biomimetics; D002454:Cell Differentiation; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D037102:Lectins / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects*; D007959:Lymphocyte Culture Test, Mixed; D009000:Monocytes / Q000276:immunology; D019158:N-Acetylneuraminic Acid / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011070:Poly I-C / Q000276:immunology; D063265:Sialic Acid Binding Immunoglobulin-like Lectins / Q000378:metabolism; D012794:Sialic Acids / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D013601:T-Lymphocytes / Q000276:immunology*; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: C000626013:Ac53FaxNeu5Ac; D015703:Antigens, CD; D000943:Antigens, Differentiation; D015214:Antigens, Differentiation, Myelomonocytic; D016207:Cytokines; D037102:Lectins; D008070:Lipopolysaccharides; C402206:SIGLEC7 protein, human; C412227:SIGLEC9 protein, human; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; D012794:Sialic Acids; D051193:Toll-Like Receptors; D019158:N-Acetylneuraminic Acid; D011070:Poly I-C