Time-resolved characterization of the mechanisms of toxicity induced by silica and amino-modified polystyrene on alveolar-like macrophages

Abstract

Macrophages play a major role in the removal of foreign materials, including nano-sized materials, such as nanomedicines and other nanoparticles, which they accumulate very efficiently. Because of this, it is recognized that for a safe development of nanotechnologies and nanomedicine, it is essential to investigate potential effects induced by nano-sized materials on macrophages. To this aim, in this work, a recently established model of primary murine alveolar-like macrophages was used to investigate macrophage responses to two well-known nanoparticle models: 50 nm amino-modified polystyrene, known to induce cell death via lysosomal damage and apoptosis in different cell types, and 50 nm silica nanoparticles, which are generally considered non-toxic. Then, a time-resolved study was performed to characterize in detail the response of the macrophages following exposure to the two nanoparticles. As expected, exposure to the amino-modified polystyrene led to cell death, but surprisingly no lysosomal swelling or apoptosis were detected. On the contrary, a peculiar mitochondrial membrane hyperpolarization was observed, accompanied by endoplasmic reticulum stress (ER stress), increased cellular reactive oxygen species (ROS) and changes of metabolic activity, ultimately leading to cell death. Strong toxic responses were observed also after exposure to silica, which included mitochondrial ROS production, mitochondrial depolarization and cell death by apoptosis. Overall, these results showed that exposure to the two nanoparticles led to a very different series of intracellular events, suggesting that the macrophages responded differently to the two nanoparticle models. Similar time-resolved studies are required to characterize the response of macrophages to nanoparticles, as a key parameter in nanosafety assessment.

Influence of polystyrene nanoparticles on the toxicity of tetrabromobisphenol A in human intestinal cell lines

“…Interestingly, we could observe a peculiar increase in ΔΨ in all the treatments containing PSNPs, leading to statistically signi cant differences with both control co-cultures and individual exposures to TBPPA. A similar condition has been reported for low doses of amine-modi ed PSNPs in primary murine macrophages (Deville et al 2020) and for PSNPs in Caco-2 cells (Cortés et al 2020), attributing it to the regulation of the mitochondrial permeability transition pore. However, Perini et al (2022) suggested that the interaction of PSNPs with phospholipid membranes can cause their hyperpolarization either by stimulating the exit of internal cations through selective pores when they adhere to the membrane surface, or by the internalization of the negatively charged PSNPs.…”

Cytotoxicity of fractured quartz on THP-1 human macrophages: role of the membranolytic activity of quartz and phagolysosome destabilization

“…In some cases, the suppression of toxicity was observed upon protein corona formation also on amorphous silica nanoparticles (Lesniak et al 2012;Tenzer et al 2013;Leibe et al 2019), but not all studies have confirmed this finding (Hsiao et al 2019;Deville et al 2020). The partial similarities between amorphous and crystalline silica may suggest the occurrence of common surface features on fractured quartz crystals and some amorphous silicas.…”

“…The interaction of the disorganized silanols with the lysosome membrane may represent the molecular initiating event (MIE) that triggers quartz cytotoxicity, as recently proposed by Pavan and Fubini ( 2017 ). These more heterogenous surfaces may be structurally similar to those of some amorphous silicas (Murashov et al 2006 ; Rimola et al 2013 ) and their occurrence may explain the cytotoxicity elicited by some amorphous silica particles after uptake and accumulation in the lysosomes (Hsiao et al 2019 ; Deville et al 2020 ). It would be interesting to study more in detail whether the different surface chemistry induced on quartz by fracturing is qualitatively comparable with the silanol pattern that occurs on the amorphous silica nanoparticle that shows cytotoxic effect.…”

In vitro inflammation and toxicity assessment of pre- and post-incinerated organomodified nanoclays to macrophages using high-throughput screening approaches

“…Mitochondrial depolarization has been described as a decision point for apoptotic signaling [ 68 ]. Past studies with nanosilica and quartz particulate exposure reported loss of MMP, increased mitochondrial ROS production, and increased apoptosis [ 69 , 70 ]. Elevated intracellular ROS appears to not play a role in THP-1 cell inflammatory or cytotoxicity responses following pre-incinerated nanoclay exposure and matches previously reported in vitro and in vivo findings [ 15 , 17 , 19 , 57 , 71 ].…”