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

Evelyne Schaeffer 1 Elena Sánchez-Fernández Rita Gonçalves-Pereira Vincent Flacher Delphine Lamon Monique Duval 2 Jean-Daniel Fauny 1 José Garcia Fernandez 3 Christopher Mueller 2 Carmen Ortiz Mellet 3
1 ICT - Immunopathologie et chimie thérapeutique
2 ICT - Immunologie et chimie thérapeutiques
3 Instituto de Investigaciones Químicas (IIQ)
Abstract : Glycolipid mimetics consisting of a bicyclic polyhydroxypiperidine-cyclic carbamate core and a pseu-doanomeric 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 lipopoly-saccharide (LPS) signaling through Toll-like receptor 4. We report that the best lead was (1R)-1-dodecylsulfonyl-5N,6O-oxomethylidenenojirimycin (DSO 2-ONJ), able to inhibit LPS-induced TNFa 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.
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Submitted on : Wednesday, December 18, 2019 - 8:47:25 PM
Last modification on : Monday, December 23, 2019 - 1:15:51 AM

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Evelyne Schaeffer, Elena Sánchez-Fernández, Rita Gonçalves-Pereira, Vincent Flacher, Delphine Lamon, et al.. sp2-Iminosugar glycolipids as inhibitors of lipopolysaccharide-mediated human dendritic cell activation in vitro and of acute inflammation in mice in vivo. European Journal of Medicinal Chemistry, Elsevier, 2019, 169, pp.111-120. ⟨10.1016/j.ejmech.2019.02.078⟩. ⟨hal-02415546⟩

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