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.

Lupus Regulator Peptide P140 Represses B Cell Differentiation by Reducing HLA Class II Molecule Overexpression

“…To further consolidate these data, we studied the possible effect of P140 on the production of the proinflammatory cytokine tumor necrosis factor α (TNFα) by DCs collected from healthy donors. The antiinflammatory mannoside glycolipid conjugate 2U was used as an internal control . The results showed that, in contrast to the effects of the 2U compound, P140 did not inhibit lipopolysaccharide‐induced production of TNFα (see Supplementary Figure 7, available on the Arthritis & Rheumatology web site at http://onlinelibrary.wiley.com/doi/10.1002/art.40470/abstract), thus further supporting the view that P140 has no effect on TLR‐4 signaling.…”

Novel carboxylate-based glycolipids: TLR4 antagonism, MD-2 binding and self-assembly properties

“…TLR4 antagonists of synthetic or natural origin can block TLR4 signaling by interacting with the natural TLR4-bound co-receptor MD-2 20 , thus competing with the natural ligand LPS. Other TLR4 inhibition mechanisms are based on preventing LPS-induced receptor co-localization and dimerization (MGCs) 21 , on interfering with cytosolic adaptor protein recruitment (TAK242) 22 , or on the direct binding with other co-receptors such as the CD14 co-receptor 23–26 .…”

sp2-Iminosugar glycolipids as inhibitors of lipopolysaccharide-mediated human dendritic cell activation in vitro and of acute inflammation in mice in vivo

“…We previously showed that the mannoside glycolipid (MGC) 9 counteracted LPS activation of DCs at similar concentrations as those now encountered for the sp 2 -IGL 3 [22]. In order to explore whether or not the two glycolipid mimics behave through similar mechanisms, a direct comparison of compound 3 with MGC 9 for their capacity to antagonize LPS in its stimulatory activity on DCs was conducted.…”