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Mechanistic Differences in Cell Death Responses to Metal-Based Engineered Nanomaterials in Kupffer Cells and Hepatocytes.

ABSTRACT: The mononuclear phagocyte system in the liver is a frequent target for nanoparticles (NPs). A toxicological profiling of metal-based NPs is performed in Kupffer cell (KC) and hepatocyte cell lines. Sixteen NPs are provided by the Nanomaterial Health Implications Research Consortium of the National Institute of Environmental Health Sciences to study the toxicological effects in KUP5 (KC) and Hepa 1-6 cells. Five NPs (Ag, CuO, ZnO, SiO₂ , and V₂ O₅ ) exhibit cytotoxicity in both cell types, while SiO₂ and V₂ O₅ induce IL-1β production in KC. Ag, CuO, and ZnO induced caspase 3 generated apoptosis in both cell types is accompanied by ion shedding and generation of mitochondrial reactive oxygen species (ROS) in both cell types. However, the cell death response to SiO₂ in KC differs by inducing pyroptosis as a result of potassium efflux, caspase 1 activation, NLRP3 inflammasome assembly, IL-1β release, and cleavage of gasdermin-D. This releases pore-performing peptide fragments responsible for pyroptotic cell swelling. Interestingly, although V₂ O₅ induces IL-1β release and delays caspase 1 activation by vanadium ion interference in membrane Na⁺ /K⁺ adenosine triphosphate (ATP)ase activity, the major cell death mechanism in KC (and Hepa 1-6) is caspase 3 mediated apoptosis. These findings improve the understanding of the mechanisms of metal-based engineered nanomaterial (ENM) toxicity in liver cells toward comprehensive safety evaluation.

SUBMITTER: Wang X

PROVIDER: S-EPMC7263057 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background & aimsComplex communications between hepatocytes and Kupffer cells (KCs) are known to drive or suppress hepatocarcinogenesis, with controversial data in the literature. In previous experiments that aimed to decipher hepatocyte/KC interactions, we unexpectedly unveiled a tumor-suppressing effect of polyinosinic-polycytidylic acid, a widely used inducer of MX dynamin like GTPase 1 (Mx1)-cre expression, which questioned a theory of interleukin 1a/6 cytokine circuit in hepatocyte/KC communication. The goal of this study was to clarify the controversy and decipher unique functions of KCs and non-KC macrophages in liver tumorigenesis.MethodsWe used the C-type lectin domain family 4 member F (Clec4f)-cre system to delete Src-homology 2 domain-containing tyrosine phosphatase 2 (Shp2)/protein tyrosine phosphatase nonreceptor 11 (Ptpn11) in KCs, and a combination of Clec4f-cre and adeno-associated virus-cre to delete Shp2 in KCs and hepatocytes to investigate the effects on hepatocellular carcinoma development and immune cell compositions/activities.ResultsAblating Shp2 in KCs generated a tumor-promoting niche, which was exacerbated further by concurrent removal of Shp2 in both KCs and hepatocytes. Shp2 deficiency induced KC apoptosis and decreased its numbers, which induced compensatory recruitment of bone marrow-derived monocytes into liver. These newly recruited monocytes differentiated into non-KC macrophages with tumor-associated macrophage function, leading to aggravated tumor progression through down-regulation of CD8 T cells. Tumor-associated macrophage blockade by anti-chemokine (C-C motif) ligand 2 (CCL2) antibody inhibited hepatocellular carcinoma progression, while depletion of all macrophages had a tumor-promoting effect by increasing myeloid-derived suppressor cells (M-MDSCs) and decreasing CD8 T cells.ConclusionsShp2 loss in KCs or hepatocytes generated a protumorigenic microenvironment, which was exacerbated by its removal in both cell types. These results show the complexity of intercellular signaling events in liver tumorigenesis and raises caution on the use of specific Shp2 inhibitor in liver cancer therapy. Transcript profiling: RNA sequencing data are available at Gene Expression Omnibus (GSE222594).

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Mechanistic Differences in Cell Death Responses to Metal-Based Engineered Nanomaterials in Kupffer Cells and Hepatocytes.

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