title: Exocytosis of macrophage lysosomes leads to digestion of apoptotic adipocytes and foam cell formation.
abstract: Many types of apoptotic cells are phagocytosed and digested by macrophages. Adipocytes can be hundreds of times larger than macrophages, so they are too large to be digested by conventional phagocytic processes. The nature of the interaction between macrophages and apoptotic adipocytes has not been studied in detail. We describe a cellular process, termed exophagy, that is important for macrophage clearance of dead adipocytes and adipose tissue homeostasis. Using mouse models of obesity, human tissue, and a cell culture model, we show that macrophages form hydrolytic extracellular compartments at points of contact with dead adipocytes using local actin polymerization. These compartments are acidic and contain lysosomal enzymes delivered by exocytosis. Uptake and complete degradation of adipocyte fragments, which are released by extracellular hydrolysis, leads to macrophage foam cell formation. Exophagy-mediated foam cell formation is a highly efficient means by which macrophages internalize large amounts of lipid, which may ultimately overwhelm the metabolic capacity of the macrophage. This process provides a mechanism for degradation of objects, such as dead adipocytes, that are too large to be phagocytosed by macrophages.
authors.affiliation: Departments of Biochemistry, Weill Cornell Medical College, New York, NY 10065.
authors.forename: Abigail S
authors.initials: AS
authors.lastname: Haka
authors.affiliation: Departments of Biochemistry, Weill Cornell Medical College, New York, NY 10065.
authors.forename: Valéria C
authors.initials: VC
authors.lastname: Barbosa-Lorenzi
authors.affiliation: Medicine, Weill Cornell Medical College, New York, NY 10065.
authors.forename: Hyuek Jong
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065.
authors.forename: Domenick J
authors.initials: DJ
authors.lastname: Falcone
authors.affiliation: Medicine, Weill Cornell Medical College, New York, NY 10065 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Hudis
authors.affiliation: Medicine, Weill Cornell Medical College, New York, NY 10065.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Dannenberg
authors.affiliation: Departments of Biochemistry, Weill Cornell Medical College, New York, NY 10065 frmaxfie@med.cornell.edu.
authors.forename: Frederick R
authors.identifier: 0000-0003-4396-8866
authors.initials: FR
authors.lastname: Maxfield
mesh_terms: D017667:Adipocytes / Q000502:physiology*; D000273:Adipose Tissue / Q000378:metabolism / Q000502:physiology; D000818:Animals; D005089:Exocytosis / Q000502:physiology*; D005487:Foam Cells / Q000473:pathology / Q000502:physiology; D006801:Humans; D008247:Lysosomes / Q000502:physiology; D008264:Macrophages / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology*; D010587:Phagocytosis / Q000502:physiology*
keywords: adipose tissue; crown-like structure; extracellular catabolism; lipolysis and fatty acid metabolism; obesity