Fiche publication
Date publication
septembre 2015
Auteurs
Membres identifiés du Cancéropôle Est :
Dr WAGNER Alain
,
Dr MUELLER Christopher
,
Dr FLACHER Vincent
Tous les auteurs :
Flacher V, Neuberg P, Point F, Daubeuf F, Muller Q, Sigwalt D, Fauny JD, Remy JS, Frossard N, Wagner A, Mueller CG, Schaeffer E
Lien Pubmed
Résumé
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 cytokines 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, prevented colocalization of CD14 and TLR4, thereby abolishing NF-kappaB 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.
Référence
ACS Chem Biol. 2015 Sep 21.
