Capacity of Metal-ions as Stimulatory Ligands in Innate Immunity

Objectives: To unravel the capacity and mechanism of low (Cr, Fe, Co, Ni, Cu, Zn) and high molecular weight (Pd, Au, Hg) transition metals to trigger the innate immune system
Methods: A panel of 8 transition metals neighboring Ni in the periodic table was tested for their capacity to trigger immature monocyte derived dendritic cells (moDC). As a read out cytokine production (a.o. IL-8, CCL-2) and phenotypic maturation was evaluated by FACS analysis. The statistical significance was analyzed by using one way ANOVA and kruskall-wallis test, with GraphPad Software version 6.0
Results: The stimulatory capacity of Ni, Co and Pd could be ascribed to TLR4 ligation. The critical role of TLR4 in this process was confirmed by essentially similar stimulatory patterns obtained in a HEK/TLR4-MD2 transfectant cell line. In contrast Au was able to trigger TLR3 and Cu strongly stimulated the wild type HEK293 cells, suggesting stimulation via TLR5, which is constitutively expressed in this cell line.
Conclusions: Like Ni, also Co can activate MoDC, whereas Pd, Cu and Zn, showed low but distinct MoDC activating potential. Both gold and mercury can induce innate immune responses, which for gold could be ascribed to TLR3 dependent signaling and for Ni, Co and Pd could be ascribed to TLR4. These responses most likely can contribute to the development of adaptive immune responses to these metals, as reflected by skin and mucosal allergies.