title: Macrophages create an acidic extracellular hydrolytic compartment to digest aggregated lipoproteins.
abstract: A critical event in atherogenesis is the interaction of macrophages with subendothelial lipoproteins. Although most studies model this interaction by incubating macrophages with monomeric lipoproteins, macrophages in vivo encounter lipoproteins that are aggregated. The physical features of the lipoproteins require distinctive mechanisms for their uptake. We show that macrophages create an extracellular, acidic, hydrolytic compartment to carry out digestion of aggregated low-density lipoproteins. We demonstrate delivery of lysosomal contents to these specialized compartments and their acidification by vacuolar ATPase, enabling aggregate catabolism by lysosomal acid hydrolases. We observe transient sealing of portions of the compartments, allowing formation of an "extracellular" proton gradient. An increase in free cholesterol is observed in aggregates contained in these compartments. Thus, cholesteryl ester hydrolysis can occur extracellularly in a specialized compartment, a lysosomal synapse, during the interaction of macrophages with aggregated low-density lipoprotein. A detailed understanding of these processes is essential for developing strategies to prevent atherosclerosis.
authors.affiliation: Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Abigail S
authors.initials: AS
authors.lastname: Haka
authors.forename: Inna
authors.initials: I
authors.lastname: Grosheva
authors.forename: Ethan
authors.initials: E
authors.lastname: Chiang
authors.forename: Adina R
authors.initials: AR
authors.lastname: Buxbaum
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Baird
authors.forename: Lynda M
authors.initials: LM
authors.lastname: Pierini
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Maxfield
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism / Q000503:physiopathology*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D002788:Cholesterol Esters / Q000378:metabolism; D005089:Exocytosis / Q000502:physiology; D005487:Foam Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D008077:Lipoproteins, LDL / Q000737:chemistry / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000502:physiology*; D051379:Mice; D010539:Permeability
chemical_list: D002788:Cholesterol Esters; D008077:Lipoproteins, LDL; D002784:Cholesterol