Mannodendrimers prevent acute lung inflammation by inhibiting neutrophil recruitment

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...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2013-05, Vol.110 (22), p.8795-8800
Main Authors: Blattes, Emilyne, Vercellone, Alain, Eutamène, Hélène, Turrin, Cédric-Olivier, Théodorou, Vassilia, Majoral, Jean-Pierre, Caminade, Anne-Marie, Prandi, Jacques, Nigou, Jérôme, Puzo, Germain
Format: Article
Language:English
Subjects:
Animals
Antiinflammatories
Bacteria
Biological Sciences
Cell adhesion & migration
Cell Adhesion Molecules - metabolism
Chemical Sciences
Coordination chemistry
Cytokines
Cytokines - antagonists & inhibitors
Cytokines - metabolism
Dendrimers
Dendrimers - chemistry
Dendrimers - pharmacology
Dendritic Cells - metabolism
Flow Cytometry
Gram-positive bacteria
Humans
Inflammatory diseases
Inhibitory concentration 50
Lectins, C-Type - metabolism
Leukocytes
Lipopolysaccharides - chemistry
Lung diseases
Lungs
Magnetic Resonance Spectroscopy
Mannosides - chemistry
Mannosides - pharmacology
Mice
Mice, Inbred C57BL
Molecular Structure
Molecules
Neutrophil infiltration
Neutrophils
Physical Sciences
Pneumonia - drug therapy
Pneumonia - pathology
Protein Binding
Receptors
Receptors, Cell Surface - metabolism
Rodents
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1221708110