TY - JOUR
T1 - Lateral size of graphene oxide determines differential cellular uptake and cell death pathways in Kupffer cells, LSECs, and hepatocytes
AU - Li, Jiulong
AU - Wang, Xiang
AU - Mei, Kuo Ching
AU - Chang, Chong Hyun
AU - Jiang, Jinhong
AU - Liu, Xiangsheng
AU - Liu, Qi
AU - Guiney, Linda M.
AU - Hersam, Mark C.
AU - Liao, Yu Pei
AU - Meng, Huan
AU - Xia, Tian
N1 - Funding Information:
The research reported in this publication was supported by the Nanotechnology Health Implications Research (NHIR) Consortium of the National Institute of Environmental Health Sciences of the National Institutes of Health under Award Number ( U01ES027237 ). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The engineered nanomaterials used in the research presented in this publication were procured/developed, characterized, and provided by the Engineered Nanomaterials Resource and Coordination Core established at Harvard T.H. Chan School of Public Health (NIH grant # U24ES026946 ) as part of the Nanotechnology Health Implications Research Consortium. The authors thank the CNSI Advanced Light Microscopy/Spectroscopy and Electron Imaging Center for NanoMachines Core Facilities, the Flow Cytometry Core Facility of Jonsson Comprehensive Cancer Center, the Microscopic Techniques and Electron Microscope Core Facility of Brain Research Institute, and the Integrated Molecular Technologies Core (CURE/P30 DK041301) at UCLA. The authors thank Xi Chen for taking the pyroptosis video. This work made use of the Keck-II facility of Northwestern University’s NUANCE Center, which has received support from the SHyNE Resource ( NSF ECCS-1542205 ), the IIN, and the Northwestern University MRSEC program ( NSF DMR-1720139 ).
Funding Information:
The research reported in this publication was supported by the Nanotechnology Health Implications Research (NHIR) Consortium of the National Institute of Environmental Health Sciences of the National Institutes of Health under Award Number (U01ES027237). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The engineered nanomaterials used in the research presented in this publication were procured/developed, characterized, and provided by the Engineered Nanomaterials Resource and Coordination Core established at Harvard T.H. Chan School of Public Health (NIH grant # U24ES026946) as part of the Nanotechnology Health Implications Research Consortium. The authors thank the CNSI Advanced Light Microscopy/Spectroscopy and Electron Imaging Center for NanoMachines Core Facilities, the Flow Cytometry Core Facility of Jonsson Comprehensive Cancer Center, the Microscopic Techniques and Electron Microscope Core Facility of Brain Research Institute, and the Integrated Molecular Technologies Core (CURE/P30 DK041301) at UCLA. The authors thank Xi Chen for taking the pyroptosis video. This work made use of the Keck-II facility of Northwestern University's NUANCE Center, which has received support from the SHyNE Resource (NSF ECCS-1542205), the IIN, and the Northwestern University MRSEC program (NSF DMR-1720139).
Publisher Copyright:
© 2020 Elsevier Ltd
PY - 2021/4
Y1 - 2021/4
N2 - As a representative two-dimensional (2D) nanomaterial, graphene oxide (GO) has shown high potential in many applications due to its large surface area, high flexibility, and excellent dispersibility in aqueous solutions. These properties make GO an ideal candidate for bio-imaging, drug delivery, and cancer therapy. When delivered to the body, GO has been shown to accumulate in the liver, the primary accumulation site of systemic delivery or secondary spread from other uptake sites, and induce liver toxicity. However, the contribution of the GO physicochemical properties and individual liver cell types to this toxicity is unclear due to property variations and diverse cell types in the liver. Herein, we compare the effects of GOs with small (GO-S) and large (GO-L) lateral sizes in three major cell types in the liver, Kupffer cells (KCs), liver sinusoidal endothelial cells (LSECs), and hepatocytes. While GOs induced cytotoxicity in KCs, they induced significantly less toxicity in LSECs and hepatocytes. For KCs, we found that GOs were phagocytosed that triggered NADPH oxidase mediated plasma membrane lipid peroxidation, which leads to PLC activation, calcium flux, mitochondrial ROS generation, and NLRP3 inflammasome activation. The subsequent caspase-1 activation induced IL-1β production and GSDMD-mediated pyroptosis. These effects were lateral size-dependent with GO-L showing stronger effects than GO-S. Amongst the liver cell types, decreased cell association and the absence of lipid peroxidation resulted in low cytotoxicity in LSECs and hepatocytes. Using additional GO samples with different lateral sizes, surface functionalities, or thickness, we further confirmed the differential cytotoxic effects in liver cells and the major role of GO lateral size in KUP5 pyroptosis by correlation studies. These findings delineated the GO effects on cellular uptake and cell death pathways in liver cells, and provide valuable information to further evaluate GO effects on the liver for biomedical applications.
AB - As a representative two-dimensional (2D) nanomaterial, graphene oxide (GO) has shown high potential in many applications due to its large surface area, high flexibility, and excellent dispersibility in aqueous solutions. These properties make GO an ideal candidate for bio-imaging, drug delivery, and cancer therapy. When delivered to the body, GO has been shown to accumulate in the liver, the primary accumulation site of systemic delivery or secondary spread from other uptake sites, and induce liver toxicity. However, the contribution of the GO physicochemical properties and individual liver cell types to this toxicity is unclear due to property variations and diverse cell types in the liver. Herein, we compare the effects of GOs with small (GO-S) and large (GO-L) lateral sizes in three major cell types in the liver, Kupffer cells (KCs), liver sinusoidal endothelial cells (LSECs), and hepatocytes. While GOs induced cytotoxicity in KCs, they induced significantly less toxicity in LSECs and hepatocytes. For KCs, we found that GOs were phagocytosed that triggered NADPH oxidase mediated plasma membrane lipid peroxidation, which leads to PLC activation, calcium flux, mitochondrial ROS generation, and NLRP3 inflammasome activation. The subsequent caspase-1 activation induced IL-1β production and GSDMD-mediated pyroptosis. These effects were lateral size-dependent with GO-L showing stronger effects than GO-S. Amongst the liver cell types, decreased cell association and the absence of lipid peroxidation resulted in low cytotoxicity in LSECs and hepatocytes. Using additional GO samples with different lateral sizes, surface functionalities, or thickness, we further confirmed the differential cytotoxic effects in liver cells and the major role of GO lateral size in KUP5 pyroptosis by correlation studies. These findings delineated the GO effects on cellular uptake and cell death pathways in liver cells, and provide valuable information to further evaluate GO effects on the liver for biomedical applications.
KW - GSDMD-dependent pyroptosis
KW - Graphene oxide
KW - Lipid peroxidation
KW - NADPH oxidase
KW - Phagocytosis
KW - Phospholipase C (PLC)
UR - http://www.scopus.com/inward/record.url?scp=85098185244&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85098185244&partnerID=8YFLogxK
U2 - 10.1016/j.nantod.2020.101061
DO - 10.1016/j.nantod.2020.101061
M3 - Article
C2 - 34055032
AN - SCOPUS:85098185244
VL - 37
JO - Nano Today
JF - Nano Today
SN - 1748-0132
M1 - 101061
ER -
