Analysis of cellular responses of macrophages to zinc ions and zinc oxide nanoparticles: a combined targeted and proteomic approach

TL;DR

This study investigates how zinc ions and zinc oxide nanoparticles affect macrophage cells, revealing their cellular uptake, impact on metabolism, protein degradation, and DNA integrity, with minimal effects on glutathione and phagocytosis.

Contribution

It combines proteomic and targeted approaches to elucidate the molecular mechanisms of zinc toxicity in macrophages, highlighting key pathways involved.

Findings

Zinc oxide nanoparticles dissolve rapidly inside cells, increasing intracellular zinc levels.

Zinc exposure alters central metabolism and proteasomal degradation pathways.

Zinc induces DNA damage but does not significantly affect glutathione or phagocytosis at moderate levels.

Abstract

Two different zinc oxide nanoparticles, as well as zinc ions, are used to study the cellular responses of the RAW 264 macrophage cell line. A proteomic screen is used to provide a wide view of the molecular effects of zinc, and the most prominent results are cross-validated by targeted studies. Furthermore, the alteration of important macrophage functions (e.g. phagocytosis) by zinc is also investigated. The intracellular dissolution/uptake of zinc is also studied to further characterize zinc toxicity. Zinc oxide nanoparticles dissolve readily in the cells, leading to high intracellular zinc concentrations, mostly as protein-bound zinc. The proteomic screen reveals a rather weak response in the oxidative stress response pathway, but a strong response both in the central metabolism and in the proteasomal protein degradation pathway. Targeted experiments confirm that carbohydrate catabolism and proteasome are critical determinants of sensitivity to zinc, which also induces DNA damage. Conversely, glutathione levels and phagocytosis appear unaffected at moderately toxic zinc concentrations.