title: Phenotype Determines Nanoparticle Uptake by Human Macrophages from Liver and Blood.
abstract: A significant challenge to delivering therapeutic doses of nanoparticles to targeted disease sites is the fact that most nanoparticles become trapped in the liver. Liver-resident macrophages, or Kupffer cells, are key cells in the hepatic sequestration of nanoparticles. However, the precise role that the macrophage phenotype plays in nanoparticle uptake is unknown. Here, we show that the human macrophage phenotype modulates hard nanoparticle uptake. Using gold nanoparticles, we examined uptake by human monocyte-derived macrophages that had been driven to a "regulatory" M2 phenotype or an "inflammatory" M1 phenotype and found that M2-type macrophages preferentially take up nanoparticles, with a clear hierarchy among the subtypes (M2c > M2 > M2a > M2b > M1). We also found that stimuli such as LPS/IFN-γ rather than with more "regulatory" stimuli such as TGF-β/IL-10 reduce per cell macrophage nanoparticle uptake by an average of 40%. Primary human Kupffer cells were found to display heterogeneous expression of M1 and M2 markers, and Kupffer cells expressing higher levels of M2 markers (CD163) take up significantly more nanoparticles than Kupffer cells expressing lower levels of surface CD163. Our results demonstrate that hepatic inflammatory microenvironments should be considered when studying liver sequestration of nanoparticles, and that modifying the hepatic microenvironment might offer a tool for enhancing or decreasing this sequestration. Our findings also suggest that models examining the nanoparticle/macrophage interaction should include studies with primary tissue macrophages.
authors.affiliation: Multi Organ Transplant Program, Toronto General Research Institute, University Health Network , 200 Elizabeth Street, Toronto, Ontario, Canada M5G 2C4.|Department of Immunology, University of Toronto , Medical Sciences Building, Room 6271, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Sonya A
authors.identifier: 0000-0002-8036-1425
authors.initials: SA
authors.lastname: MacParland
authors.affiliation: Institute of Biomaterials and Biomedical Engineering, University of Toronto , Rosebrugh Building, Room 407, 164 College Street, Toronto, Ontario, Canada M5S 3G9.|Division of Orthopaedic Surgery, University of Toronto , 149 College Street, Toronto, Ontario, Canada M5T 1P5.
authors.forename: Kim M
authors.initials: KM
authors.lastname: Tsoi
authors.affiliation: Institute of Biomaterials and Biomedical Engineering, University of Toronto , Rosebrugh Building, Room 407, 164 College Street, Toronto, Ontario, Canada M5S 3G9.
authors.forename: Ben
authors.initials: B
authors.lastname: Ouyang
authors.affiliation: Multi Organ Transplant Program, Toronto General Research Institute, University Health Network , 200 Elizabeth Street, Toronto, Ontario, Canada M5G 2C4.
authors.forename: Xue-Zhong
authors.initials: XZ
authors.lastname: Ma
authors.affiliation: Multi Organ Transplant Program, Toronto General Research Institute, University Health Network , 200 Elizabeth Street, Toronto, Ontario, Canada M5G 2C4.
authors.forename: Justin
authors.initials: J
authors.lastname: Manuel
authors.affiliation: Department of Immunology, University of Toronto , Medical Sciences Building, Room 6271, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Ali
authors.initials: A
authors.lastname: Fawaz
authors.affiliation: Department of Immunology, University of Toronto , Medical Sciences Building, Room 6271, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Mario A
authors.initials: MA
authors.lastname: Ostrowski
authors.affiliation: Department of Orthopaedic Surgery, Duke University , Duke University Medical Center, Room 2888, 200 Trent Drive, Durham, North Carolina 27710, United States.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Alman
authors.affiliation: Department of Physics, University of Toronto , 60 St. George Street, Toronto, Ontario, Canada M5S 1A7.
authors.forename: Anton
authors.initials: A
authors.lastname: Zilman
authors.affiliation: Institute of Biomaterials and Biomedical Engineering, University of Toronto , Rosebrugh Building, Room 407, 164 College Street, Toronto, Ontario, Canada M5S 3G9.|Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto , 160 College Street, Room 230, Toronto, Ontario, Canada M5S 3E1.|Department of Chemical Engineering, University of Toronto , 200 College Street, Toronto, Ontario, Canada M5S 3E5.|Department of Chemistry, University of Toronto , 80 St. George Street, Toronto, Ontario, Canada M5S 3H6.|Department of Material Science and Engineering, University of Toronto , 160 College Street, Room 450, Toronto, Ontario, Canada M5S 3E1.
authors.forename: Warren C W
authors.initials: WC
authors.lastname: Chan
authors.affiliation: Multi Organ Transplant Program, Toronto General Research Institute, University Health Network , 200 Elizabeth Street, Toronto, Ontario, Canada M5G 2C4.
authors.forename: Ian D
authors.identifier: 0000-0003-4649-546X
authors.initials: ID
authors.lastname: McGilvray
mesh_terms: D006046:Gold / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008264:Macrophages / Q000737:chemistry / Q000378:metabolism*; D053768:Metal Nanoparticles / Q000737:chemistry*; D009000:Monocytes / Q000737:chemistry / Q000378:metabolism; D010641:Phenotype
chemical_list: D006046:Gold
keywords: Kupffer cell; cytokine; macrophage; nanoparticle; phagocytosis; phenotype