title: Crucial Role of Lateral Size for Graphene Oxide in Activating Macrophages and Stimulating Pro-inflammatory Responses in Cells and Animals.
abstract: Graphene oxide (GO) is increasingly used in biomedical applications because it possesses not only the unique properties of graphene including large surface area and flexibility but also hydrophilicity and dispersibility in aqueous solutions. However, there are conflicting results on its biocompatibility and biosafety partially due to large variations in physicochemical properties of GO, and the role of these properties including lateral size in the biological or toxicological effects of GO is still unclear. In this study, we focused on the role of lateral size by preparing a panel of GO samples with differential lateral sizes using the same starting material. We found that, in comparison to its smaller counterpart, larger GO showed a stronger adsorption onto the plasma membrane with less phagocytosis, which elicited more robust interaction with toll-like receptors and more potent activation of NF-κB pathways. By contrast, smaller GO sheets were more likely taken up by cells. As a result, larger GO promoted greater M1 polarization, associated with enhanced production of inflammatory cytokines and recruitment of immune cells. The in vitro results correlated well with local and systemic inflammatory responses after GO administration into the abdominal cavity, lung, or bloodstream through the tail vein. Together, our study delineated the size-dependent M1 induction of macrophages and pro-inflammatory responses of GO in vitro and in vivo. Our data also unearthed the detailed mechanism underlying these effects: a size-dependent interaction between GO and the plasma membrane.
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: Juan
authors.initials: J
authors.lastname: Ma
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: Rui
authors.initials: R
authors.lastname: Liu
authors.affiliation: Division of NanoMedicine, Department of Medicine, University of California , Los Angeles, California 90095, United States.
authors.forename: Xiang
authors.initials: X
authors.lastname: Wang
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: Qian
authors.initials: Q
authors.lastname: Liu
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: Yunan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Mechanical Engineering, University of Hawaii at Manoa , Honolulu, Hawaii 96822, United States.
authors.forename: Russell P
authors.initials: RP
authors.lastname: Valle
authors.affiliation: Department of Mechanical Engineering, University of Hawaii at Manoa , Honolulu, Hawaii 96822, United States.
authors.forename: Yi Y
authors.initials: YY
authors.lastname: Zuo
authors.affiliation: Division of NanoMedicine, Department of Medicine, University of California , Los Angeles, California 90095, United States.
authors.forename: Tian
authors.initials: T
authors.lastname: Xia
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: Sijin
authors.initials: S
authors.lastname: Liu
mesh_terms: D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000276:immunology; D006108:Graphite / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology* / Q000633:toxicity; D006801:Humans; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000276:immunology; D049329:Nanostructures / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity; D010087:Oxides / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology* / Q000633:toxicity; D010587:Phagocytosis / Q000187:drug effects; D051193:Toll-Like Receptors / Q000276:immunology
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D010087:Oxides; D051193:Toll-Like Receptors; D006108:Graphite
keywords: graphene oxide; macrophages; nanotoxicology; plasma membrane; pro-inflammatory responses