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

Abstract Glycolipid mimetics consisting of a bicyclic polyhydroxypiperidine-cyclic carbamate core and a pseudoanomeric hydrophobic tail, termed sp 2 -iminosugar glycolipids (sp 2 -IGLs), target microglia during neuroinflammatory processes. Here we have synthesized and investigated new variants of sp 2 -IGLs for their ability to suppress the activation of human monocyte-derived dendritic cells (DCs) by lipopolysaccharide (LPS) signaling through Toll-like receptor 4. We report that the best lead was (1 R )-1-dodecylsulfonyl-5 N ,6 O -oxomethylidenenojirimycin (DSO 2 -ONJ), able to inhibit LPS-induced TNFα production and maturation of DCs. Immunovisualization experiments, using a mannoside glycolipid conjugate (MGC) that also suppress LPS-mediated DC activation as control, evidenced a distinct mode of action for the sp 2 -IGLs: unlike MGCs, DSO 2 -ONJ did not elicit internalization of the LPS co-receptor CD14 or induce its co-localization with the Toll-like receptor 4. In a mouse model of LPS-induced acute inflammation, DSO 2 -ONJ demonstrated anti-inflammatory activity by inhibiting the production of the pro-inflammatory interleukin-6. The ensemble of the data highlights sp 2 -IGLs as a promising new class of molecules against inflammation by interfering in Toll-like receptor intracellular signaling.