Allergy-Protective Arabinogalactan Modulates Human Dendritic Cells via C-Type Lectins and Inhibition of NF-κB

Abstract

Arabinogalactan (AG) isolated from dust of a traditional farm prevents disease in murine models of allergy. However, it is unclear whether this polysaccharide has immune regulatory properties in humans. The aim of this study was to test the influence of AG on the immune-stimulating properties of human dendritic cells (DCs). Moreover, we sought to identify the receptor to which AG binds. AG was produced from plant callus tissue under sterile conditions to avoid the influence of pathogen-associated molecular patterns in subsequent experiments. The influence of AG on the human immune system was investigated by analyzing its impact on monocyte-derived DCs. To analyze whether the T cell stimulatory capacity of AG-stimulated DCs is altered, an MLR with naive Th cells was performed. We revealed that AG reduced T cell proliferation in a human MLR. In the search for a molecular mechanism, we found that AG binds to the immune modulatory receptors DC-specific ICAM-3–grabbing non integrin (DC-SIGN) and macrophage mannose receptor 1 (MMR-1). Stimulation of these receptors with AG simultaneously with TLR4 stimulation with LPS increased the expression of the E3 ubiquitin-protein ligase tripartite motif–containing protein 21 and decreased the phosphorylation of NF-κB p65 in DCs. This led to a reduced activation profile with reduced costimulatory molecules and proinflammatory cytokine production. Blocking of MMR-1 or DC-SIGN with neutralizing Abs partially inhibits this effect. We conclude that AG dampens the activation of human DCs by LPS via binding to DC-SIGN and MMR-1, leading to attenuated TLR signaling. This results in a reduced T cell activation capacity of DCs.

Immethridine, histamine H3-receptor (H3R) agonist, alleviated experimental autoimmune encephalomyelitis via inhibiting the function of dendritic cells

“…The ability of antigen presentation of DCs was assayed in vitro and the results indicated the treatment of immethridine reduced the function of antigen presentation and the inhibitory effect has also been detected in MLR assay. The maturation of DCs could be induced by LPS stimulation via activating NF-κB or MAPK signaling pathway [ 39 , 40 ]. To understand what kind of signaling pathway was involved in the function of immethridine, the signaling pathway of NF-κB and MAPK was analyzed and the results indicated that immethridine could reduce the expression of TLR-4 and CD14, which are receptor or co-receptor of LPS, and down-regulate the phosphorylation of NF-κB p65 but not ERK1/2.…”

A patent on the synthesis of arabino‐oligosaccharides for regulation of immune responses in the lung

“…Subsequently, DCs have reduced ability to stimulate T lymphocytes. 6 Therefore, it was discussed that inhalation of AG could result in a dampened Th2 cell activation in the lung, thus leading to a reduced allergic sensitization via the airways.…”

“…7 The AG molecule is large with a molecular mass of 127 kDa. 6 Due to its high mass and structural complexity, the complete chemical synthesis of this molecule is impossible. However, experiments, in which the arabinose side chains were cleaved, suggested that these residues are critically involved in the immune modulatory activity of the molecule.…”

“…We showed that AG binds to c‐type lectin receptors on human DCs leads to the down‐regulation of cellular activation by extracellular stimuli like for instance lipopolysaccharide. Subsequently, DCs have reduced ability to stimulate T lymphocytes . Therefore, it was discussed that inhalation of AG could result in a dampened Th2 cell activation in the lung, thus leading to a reduced allergic sensitization via the airways.…”

Pseudo-Mannosylated DC-SIGN Ligands as Immunomodulants

“… 9 ). Notably, different DC-SIGN ligands are known to induce distinct intracellular signaling pathways and immunological outcomes, supporting an important role for DC-SIGN as a target for immunomodulatory approaches 10 11 12 13 . Finally, thanks to its antigen uptake and signaling properties, DC-SIGN is a promising candidate for the development of vaccines targeting DCs 14 15 .…”