title: Murine bone marrow-derived macrophages differentiated with GM-CSF become foam cells by PI3Kγ-dependent fluid-phase pinocytosis of native LDL.
abstract: Accumulation of cholesterol by macrophage uptake of LDL is a key event in the formation of atherosclerotic plaques. Previous research has shown that granulocyte-macrophage colony-stimulating factor (GM-CSF) is present in atherosclerotic plaques and promotes aortic lipid accumulation. However, it has not been determined whether murine GM-CSF-differentiated macrophages take up LDL to become foam cells. GM-CSF-differentiated macrophages from LDL receptor-null mice were incubated with LDL, resulting in massive macrophage cholesterol accumulation. Incubation of LDL receptor-null or wild-type macrophages with increasing concentrations of ¹²⁵I-LDL showed nonsaturable macrophage LDL uptake that was linearly related to the amount of LDL added, indicating that LDL uptake was mediated by fluid-phase pinocytosis. Previous studies suggest that phosphoinositide 3-kinases (PI3K) mediate macrophage fluid-phase pinocytosis, although the isoform mediating this process has not been determined. Because PI3Kγ is known to promote aortic lipid accumulation, we investigated its role in mediating macrophage fluid-phase pinocytosis of LDL. Wild-type macrophages incubated with LDL and the PI3Kγ inhibitor AS605240 or PI3Kγ-null macrophages incubated with LDL showed an ∼50% reduction in LDL uptake and cholesterol accumulation compared with wild-type macrophages incubated with LDL only. These results show that GM-CSF-differentiated murine macrophages become foam cells by fluid-phase pinocytosis of LDL and identify PI3Kγ as contributing to this process.
authors: Section of Experimental Atherosclerosis, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors: Joshua J
authors: JJ
authors: Anzinger
authors: Janet
authors: J
authors: Chang
authors: Qing
authors: Q
authors: Xu
authors: Manoj K
authors: MK
authors: Barthwal
authors: Thomas
authors: T
authors: Bohnacker
authors: Matthias P
authors: MP
authors: Wymann
authors: Howard S
authors: HS
authors: Kruth
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D008078:Cholesterol, LDL / Q000378:metabolism*; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000502:physiology*; D005487:Foam Cells / Q000187:drug effects / Q000502:physiology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008077:Lipoproteins, LDL; D008264:Macrophages / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010873:Pinocytosis / Q000187:drug effects*; D011810:Quinoxalines / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: C505144:5-quinoxalin-6-ylmethylenethiazolidine-2,4-dione; D008078:Cholesterol, LDL; D008077:Lipoproteins, LDL; D011810:Quinoxalines; D045162:Thiazolidinediones; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse