ABSTRACT
We are thus directly and repeatedly exposed to such materials in our daily life, through inhalation, ingestion, dermal contact and injection. Upon exposure, NPs may be translocated into the body via the skin, the GI tract, the upper respiratory tract or the lung by crossing epithelial barriers. For medical purposes, NPs may also be administered parenterally. The small size of NPs (they must be at least in one dimension less than 100 nm in size) facilitates their uptake into cells as well as transcytosis across epithelial cells into blood and lymph circulation, to reach different sites, such as the central nervous system.1 The growing use of nanomaterials has raised public concern about their potential risks to human health, since the safety of these compounds has not been fully assessed, partly because nanomaterials have been considered as safe as common larger sized materials, which are not absorbed by the body. Could Nanotechnology be dangerous? Indeed, many nanomaterials are based on molecules, which are, per se, toxic; others are non-degradable and if humans are exposed to these materials, they can potentially accumulate in organs with unknown effects. Others, because of their surface properties or quantum effects, can have a catalytic activity that may interfere with biological processes. In some cases, the nano form may facilitate the uptake of molecules or ions at the cellular or body level that would otherwise not be possible, with toxicological consequences. In particular, NPs are able to influence the immune system of the host, and immune organs have been shown to be the main sites for the deposition of some NPs following systemic exposure.2 Once inside the cell, NPs accumulate in compartments like endosomes and lysosomes. Before any cyto-or genotoxic event takes place, NPs are likely to induce immune responses, involving the activation of biochemical (e.g., complement cascade) and cellular components of the immune system. It is a well-known fact that macrophages play a key role in this process,3 but the exact events that occur in the interaction between the NPs and the immune cells are still largely unknown, and results are often contradictory, mainly due to a lack of standardisation, both in methods and in reagents.4,5 In this regard, efforts have been made in order to standardise protocols, for assessing NP interaction with the immune system and its potential effects on their biodistribution.6,7
NP toxicity is generally described in terms of oxidative stress, inflammation, adjuvant and procoagulant effects, and interaction with biomolecules that might lead to unwanted toxic effects in the body.8,9 In this regard, it has been described that the association of the NPs with biological molecules such as bacterial endotoxins can strongly affect the immune response towards these materials.10Moreover, the diverse surface molecules, such as dextrans, citrate, synthetic polymers or phospholipids, used as an attempt to improve the biocompatibility of the NPs, result in highly differing physico-chemical properties and interactions of the particles with the cells.11 It should be also taken into account that alterations in the properties of the NPs can also occur when these compounds come in contact with the body or biological entities present in the environment, modifying the nanomaterial and causing dissolution, aggregation or coating of the NPs. The results of these potential alterations in the NPs range from free ions and chemicals released in the body to micrometre-sized aggregates.5,12 In this regard, it is a well-known fact that an NP introduced into a biological system may rapidly adsorb proteins, forming a “protein corona”, which surrounds the individual NPs and is responsible for the inter-particle aggregation.13,14 The direct toxicity of NPs in different human cells in vitro has been addressed in several papers,15-22 but studying the interaction of the NPs with the immune system is particularly relevant in the case of NPs used for biomedical purposes, since these compounds are often injected into the blood stream and in direct contact with many immune cell types.23 The first cells to come in contact with injected NPs are leukocytes, such as lymphocytes and monocytes/macrophages, and in the case of ingested or inhaled NPs, the response of non-professional defence cells (such as human gut and lung epithelial cells) can be considered as representative of the real life situation.24 In this review, we summarise the information available about the effects of metallic and metal oxide NPs in the immune response of the host, ranging from the apoptosis (programmed cell death) of single cells to the recruitment of immune cells to the lungs and the associated cytokine production, cell proliferation, activation of intracellular signalling pathways and genotoxicity.
