title: Mannoside Glycolipid Conjugates Display Anti-inflammatory Activity by Inhibition of Toll-like Receptor-4 Mediated Cell Activation.
abstract: Inhibition of excessive Toll-like receptor 4 (TLR4) signaling is a therapeutic approach pursued for many inflammatory diseases. We report that Mannoside Glycolipid Conjugates (MGCs) selectively blocked TLR4-mediated activation of human monocytes and monocyte-derived dendritic cells (DCs) by lipopolysaccharide (LPS). They potently suppressed pro-inflammatory cytokine secretion and maturation of DCs exposed to LPS, leading to impaired T cell stimulation. MGCs did not interfere with LPS and could act in a delayed manner, hours after LPS stimulation. Their inhibitory action required both the sugar heads and the lipid chain, although the nature of the sugar and the structure of the lipid tail could be modified. They blocked early signaling events at the cell membrane, enhanced internalization of CD14 receptors, and prevented colocalization of CD14 and TLR4, thereby abolishing NF-κB nuclear translocation. When the best lead conjugate was tested in a mouse model of LPS-induced acute lung inflammation, it displayed an anti-inflammatory action by suppressing the recruitment of neutrophils. Thus, MGCs could serve as promising leads for the development of selective TLR4 antagonistic agents for inflammatory diseases.
authors.affiliation: Laboratory of Immunopathology and Therapeutic Chemistry, CNRS UPR 3572/Laboratory of Excellence MEDALIS, Institut de Biologie Moléculaire et Cellulaire , 15 rue René Descartes, 67000 Strasbourg, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Flacher
authors.forename: Patrick
authors.initials: P
authors.lastname: Neuberg
authors.affiliation: Laboratory of Immunopathology and Therapeutic Chemistry, CNRS UPR 3572/Laboratory of Excellence MEDALIS, Institut de Biologie Moléculaire et Cellulaire , 15 rue René Descartes, 67000 Strasbourg, France.
authors.forename: Floriane
authors.initials: F
authors.lastname: Point
authors.affiliation: Laboratory of Therapeutic Innovation, CNRS-University of Strasbourg UMR 7200/Laboratory of Excellence MEDALIS, Faculté de Pharmacie, Université de Strasbourg , 74 route du Rhin, 67400 Illkirch, France.
authors.forename: François
authors.initials: F
authors.lastname: Daubeuf
authors.affiliation: Laboratory of Immunopathology and Therapeutic Chemistry, CNRS UPR 3572/Laboratory of Excellence MEDALIS, Institut de Biologie Moléculaire et Cellulaire , 15 rue René Descartes, 67000 Strasbourg, France.
authors.forename: Quentin
authors.initials: Q
authors.lastname: Muller
authors.forename: David
authors.initials: D
authors.lastname: Sigwalt
authors.affiliation: Laboratory of Immunopathology and Therapeutic Chemistry, CNRS UPR 3572/Laboratory of Excellence MEDALIS, Institut de Biologie Moléculaire et Cellulaire , 15 rue René Descartes, 67000 Strasbourg, France.
authors.forename: Jean-Daniel
authors.initials: JD
authors.lastname: Fauny
authors.forename: Jean-Serge
authors.initials: JS
authors.lastname: Remy
authors.affiliation: Laboratory of Therapeutic Innovation, CNRS-University of Strasbourg UMR 7200/Laboratory of Excellence MEDALIS, Faculté de Pharmacie, Université de Strasbourg , 74 route du Rhin, 67400 Illkirch, France.
authors.forename: Nelly
authors.initials: N
authors.lastname: Frossard
authors.forename: Alain
authors.initials: A
authors.lastname: Wagner
authors.affiliation: Laboratory of Immunopathology and Therapeutic Chemistry, CNRS UPR 3572/Laboratory of Excellence MEDALIS, Institut de Biologie Moléculaire et Cellulaire , 15 rue René Descartes, 67000 Strasbourg, France.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Mueller
authors.affiliation: Laboratory of Immunopathology and Therapeutic Chemistry, CNRS UPR 3572/Laboratory of Excellence MEDALIS, Institut de Biologie Moléculaire et Cellulaire , 15 rue René Descartes, 67000 Strasbourg, France.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Schaeffer
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002240:Carbohydrate Sequence; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects; D006017:Glycolipids / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008070:Lipopolysaccharides; D008362:Mannosides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D011014:Pneumonia / Q000139:chemically induced / Q000188:drug therapy; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors*; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D000893:Anti-Inflammatory Agents; D006017:Glycolipids; D008070:Lipopolysaccharides; D008362:Mannosides; D017346:Protein Serine-Threonine Kinases; D051197:Toll-Like Receptor 4; D000097782:NF-kappaB-Inducing Kinase