title: Mannodendrimers prevent acute lung inflammation by inhibiting neutrophil recruitment.
abstract: Mycobacterium tuberculosis mannose-capped lipoarabinomannan inhibits the release of proinflammatory cytokines by LPS-stimulated human dendritic cells (DCs) via targeting the C-type lectin receptor DC-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN). With the aim of mimicking the bioactive supramolecular structure of mannose-capped lipoarabinomannan, we designed and synthesized a set of poly(phosphorhydrazone) dendrimers grafted with mannose units, called mannodendrimers, that differed by size and the number and length of their (α1→2)-oligommanoside caps. A third-generation dendrimer bearing 48 trimannoside caps (3T) and a fourth-generation dendrimer bearing 96 dimannosides (4D) displayed the highest binding avidity for DC-SIGN. Moreover, these dendrimers inhibited proinflammatory cytokines, including TNF-α, production by LPS-stimulated DCs in a DC-SIGN-dependent fashion. Finally, in a model of acute lung inflammation in which mice were exposed to aerosolized LPS, per os administration of 3T mannodendrimer was found to significantly reduce neutrophil influx via targeting the DC-SIGN murine homolog SIGN-related 1. The 3T mannodendrimer therefore represents an innovative fully synthetic compound for the treatment of lung inflammatory diseases.
authors.affiliation: Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, F-31077 Toulouse, France.
authors.forename: Emilyne
authors.initials: E
authors.lastname: Blattes
authors.forename: Alain
authors.initials: A
authors.lastname: Vercellone
authors.forename: Hélène
authors.initials: H
authors.lastname: Eutamène
authors.forename: Cédric-Olivier
authors.initials: CO
authors.lastname: Turrin
authors.forename: Vassilia
authors.initials: V
authors.lastname: Théodorou
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Majoral
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Caminade
authors.forename: Jacques
authors.initials: J
authors.lastname: Prandi
authors.forename: Jérôme
authors.initials: J
authors.lastname: Nigou
authors.forename: Germain
authors.initials: G
authors.lastname: Puzo
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism; D050091:Dendrimers / Q000737:chemistry / Q000494:pharmacology*; D003713:Dendritic Cells / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D037181:Lectins, C-Type / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008362:Mannosides / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D011014:Pneumonia / Q000188:drug therapy* / Q000473:pathology; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000378:metabolism*; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D015815:Cell Adhesion Molecules; D016207:Cytokines; D050091:Dendrimers; D037181:Lectins, C-Type; D008070:Lipopolysaccharides; D008362:Mannosides; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C050016:lipoarabinomannan
keywords: ManLAM functional analogs; SIGNR1 targeting; antiinflammatory molecule; glycodendrimer synthesis; multivalent ligands