title: Graphene oxide induces toll-like receptor 4 (TLR4)-dependent necrosis in macrophages.
abstract: Graphene and graphene-based nanomaterials display novel and beneficial chemical, electrical, mechanical, and optical characteristics, which endow these nanomaterials with promising applications in a wide spectrum of areas such as electronics and biomedicine. However, its toxicity on health remains unknown and is of great concern. In the present study, we demonstrated that graphene oxide (GO) induced necrotic cell death to macrophages. This toxicity is mediated by activation of toll-like receptor 4 (TLR4) signaling and subsequently in part via autocrine TNF-α production. Inhibition of TLR4 signaling with a selective inhibitor prevented cell death nearly completely. Furthermore, TLR4-deficient bone marrow-derived macrophages were resistant to GO-triggered necrosis. Similarly, GO did not induce necrosis of HEK293T/TLR4-null cells. Macrophagic cell death upon GO treatment was partially attributed to RIP1-RIP3 complex-mediated programmed necrosis downstream of TNF-α induction. Additionally, upon uptake into macrophages, GO accumulated primarily in cytoplasm causing dramatic morphologic alterations and a significant reduction of the macrophagic ability in phagocytosis. However, macrophagic uptake of GO may not be required for induction of necrosis. GO exposure also caused a large increase of intracellular reactive oxygen species (ROS), which contributed to the cause of cell death. The combined data reveal that interaction of GO with TLR4 is the predominant molecular mechanism underlying GO-induced macrophagic necrosis; also, cytoskeletal damage and oxidative stress contribute to decreased viability and function of macrophages upon GO treatment.
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
authors.forename: Guangbo
authors.initials: G
authors.lastname: Qu
authors.forename: Sijin
authors.initials: S
authors.lastname: Liu
authors.forename: Shuping
authors.initials: S
authors.lastname: Zhang
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wang
authors.forename: Bingbing
authors.initials: B
authors.lastname: Sun
authors.forename: Nuoya
authors.initials: N
authors.lastname: Yin
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.forename: Tian
authors.initials: T
authors.lastname: Xia
authors.forename: Jane-Jane
authors.initials: JJ
authors.lastname: Chen
authors.forename: Gui-Bin
authors.initials: GB
authors.lastname: Jiang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D006108:Graphite / Q000009:adverse effects*; D057809:HEK293 Cells; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000473:pathology*; D008422:Materials Testing; D051379:Mice; D053758:Nanoparticles / Q000009:adverse effects*; D009336:Necrosis / Q000139:chemically induced / Q000473:pathology; D010087:Oxides / Q000009:adverse effects
chemical_list: D010087:Oxides; D006108:Graphite