Particulate β-glucans synergistically activate TLR4 and Dectin-1 in human dendritic cells

Scope: The major receptor for beta(1-3)-glucans on immune cells is considered to be Dectin-1 receptor. Particulate beta-glucans induce stronger immune responses than soluble beta-glucans by clustering of Dectin-1 receptors. Here, it was hypothesized that activation of other pattern recognition receptors such as Toll-like receptor 4 (TLR4) can also contribute to enhanced activity of immune cells after exposure to particulate beta-glucans. Methods and results: To test this hypothesis, reporter cell lines were designed expressing TLR4 with either Dectin-1A or Dectin-1B, that is, one of the two transcript variants of human Dectin-1 receptors. Enhanced NF-kappa B activation was observed after stimulation with particulate beta-glucans in both Dectin-1A-TLR4 and the Dectin-1B-TLR4 cell lines. This was different with soluble beta-glucans, which enhanced activation in Dectin-1A-TLR4 cell lines but not in Dectin-1B-TLR4 cells. The synergistic activation of TLR4 and Dectin-1 by particulate beta-glucans was confirmed in human dendritic cells. The effects of particulate beta-glucan induced TLR4 binding were regulatory as blocking TLR4 enhanced pro-inflammatory cytokine IL-23, IL-4, IL-6, and TNF-alpha production. Conclusion: These results suggest that TLR4 and Dectin-1 are synergistically activated by particulate beta-glucans, wherein TLR4 activates an immune regulatory pathway in human dendritic cells. Our data suggest that beta-glucan is an immune regulatory ligand for TLR4.