The effect of nanoparticles (NPs) of photoactive zinc and titanium oxides on innate immunity is unknown, despite the advent of new transparent sunscreens containing these nanomaterials. This is important as tissue resident immune cells in the skin are the first point of contact where sunscreen NPs can be actively sequestered by cells. Therefore, in this project I investigated the effect that these NPs have on the function of cellular elements of the innate immune system, including monocytes, macrophages, and Langerhans cells (LCs). Although zinc oxide (ZnO) NPs are widely used in sunscreens, the relationship between ROS generation, zinc ion release and cytotoxicity caused by these particles, is not clearly understood. The first part of this project explored whether these factors could be accurately quantified and related. This study demonstrated a strong correlation between ZnO NP-induced cytotoxicity and free intracellular zinc concentration in human immune cells, indicating a requirement for NP dissolution to precede cytotoxicity. The elevated ROS levels present in NP-exposed cells also correlated to both cytotoxicity and intracellular free zinc. Although the addition of antioxidants was able to reduce ROS, cytotoxicity to ZnO NPs was unaffected – this suggested that ROS may be, in part, a result of cytotoxicity rather than solely as a causal factor for cytotoxicity. This study highlights both the requirement and role of intracellular dissolution of zinc nanomaterials in eliciting a cytotoxic response. Therefore, modification of NP uptake and their intracellular solubility are key components in modulating the bioactivity of ZnO NPs. The second part of this project compared the ROS generation by UVA and sunscreen NPs in human immune cells. Although it is known that ROS generation occurs in cells exposed to ZnO and TiO2 NPs, it is unknown to what extent this ROS generation is altered with UVA co-exposure. Furthermore, ZnO and TiO2 NPs in sunscreens themselves attenuate the oxidative damage to cells and tissues from free radicals induced by UVA irradiation. In order to determine the relative hazard potential of UVA co-exposure with nanosunscreen NPs, ROS generation was investigated in human THP-1 monocyte immune cells co-exposed to UVA and NPs. This study indicates that ROS generation from nanosunscreens is, with the exception of anatase TiO2 NPs, an insignificant contributor to the overall hazard associated with oxidative stress from UVA exposure itself. In the third part of this project, the effect of ZnO NPs on the function of LCs was investigated. This study found that ZnO NPs can simultaneously cause pro-inflammatory and anti-inflammatory effects in these antigen presenting cells. In addition, ZnO NPs altered the release of bioactive molecules (cytokines) from immune cells, suppressed antigen processing and presentation, and stimulated lymphocyte proliferation. This study indicates that ZnO NPs may modulate antigen presentation processes that can lead to allergic reactions. In conclusion, sunscreen ZnO and TiO2 NPs are well tolerated by skin immune cells, with ZnO only causing cytotoxicity at very high concentrations. Also, ZnO NPs possess immunomodulatory effects that provide further evidence of the mode of action in the therapeutic topical use of zinc
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