Toxicological Profiling of Metal Oxide Nanoparticles in Liver Context Reveals Pyroptosis in Kupffer Cells and Macrophages versus Apoptosis in Hepatocytes

Abstract

The liver and the mononuclear phagocyte system are a frequent target for engineered nanomaterials, either as a result of particle uptake and spread from primary exposure sites or systemic administration of therapeutic and imaging nanoparticles. In this study, we performed a comparative analysis of the toxicological impact of 29 metal oxide nanoparticles (NPs), some commonly used in consumer products, in transformed or primary Kupffer cells (KCs) and hepatocytes. We not only observed differences between KCs and hepatocytes, but also differences in the toxicological profiles of transition-metal oxides (TMOs, e. g., CoO) versus rare-earth oxide (REO) NPs ( e. g., GdO). While pro-oxidative TMOs induced the activation of caspases 3 and 7, resulting in apoptotic cell death in both cell types, REOs induced lysosomal damage, NLRP3 inflammasome activation, caspase 1 activation, and pyroptosis in KCs. Pyroptosis was accompanied by cell swelling, membrane blebbing, IL-1β release, and increased membrane permeability, which could be reversed by knockdown of the pore forming protein, gasdermin D. Though similar features were not seen in hepatocytes, the investigation of the cytotoxic effects of REO NPs could also be seen to affect macrophage cell lines such as J774A.1 and RAW 264.7 cells as well as bone marrow-derived macrophages. These phagocytic cell types also demonstrated features of pyroptosis and increased IL-1β production. Collectively, these findings demonstrate important mechanistic considerations that can be used for safety evaluation of metal oxides, including commercial products that are developed from these materials.

Nanoparticles and danger signals: Oral delivery vehicles as potential disruptors of intestinal barrier homeostasis

“…As intracellular NP accumulation can result in cell death through both necrotic and pyroptotic pathways, this also allows free mtDNA and whole mitochondria to act as a danger signals when released from dying cells into the extracellular space . Should dying cells and/or their released cellular components be phagocytized, mtDNA is capable of binding to TLR9, an endosomal pattern recognition receptor (PRR) that recognizes unmethylated CpG sequences on DNA.…”

“…It has been previously well described that the reactivities of different NPs are influenced by their chemical composition. This is dependent on different classes of NPs—such as transition metal oxides, soluble metal oxides, cationic/anionic liposomes, and others— as well as size, added particle coatings, and functional groups, crystalline vs. amorphous structure, and acquired biocoronas . Recent studies are shedding more light on exactly how these different chemical compositions interact with cells and subcellular components, with evidence suggesting that responses may not only be NP‐specific, but also cell‐type specific …”

Anti‐Infective Application of Graphene‐Like Silicon Nanosheets via Membrane Destruction

“…However, their practical applications are hindered by their potential cytotoxicity, which often causes inflammation and irritation. Moreover, the antibacterial agents that are often used include traditional antibiotics and some metal nanoparticles such as silver, copper, and magnesium, which are limited by bacterial drug resistance and the potential toxic side effects of the metal ions, respectively . Therefore, biomaterials with better antibacterial properties and biocompatibility are urgently needed.…”

Iron Oxide Nanoparticle-Induced Autophagic Flux Is Regulated by Interplay between p53-mTOR Axis and Bcl-2 Signaling in Hepatic Cells

“…Surprisingly, in literature there are very few reports about responses of hepatic cells to sub-lethal treatment with NPs, for review see [19]. Moreover, most of the research is done utilizing only one cell line without direct comparison of the observed effects on closely related cell lines [16,19,20]. Therefore, in this study, we chose three hepatic cell lines (HepG2, Huh7, and Alexander cells).…”