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.
Highlights
Many types of apoptotic cells are phagocytosed and digested by macrophages
To see whether exophagy occurs during macrophage interactions with dead adipocytes, we first examined the amount of lysosome exocytosis in cells (green) surrounding (CLS) and resident macrophages in an established mouse model of obesity
In white adipose tissue (WAT) of obese mice, in human tissue, and in a CLS cell culture model, we found that CLS macrophages use F-actinrich protrusions to create extracellular digestive compartments at the macrophage-adipocyte interface
Summary
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. 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. Exophagy-mediated foam cell formation is a highly efficient means by which macrophages internalize large amounts of lipid, which may 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.—Haka, A. In this study, we show that, rather than endocytosis of released lipids, the macrophages themselves actively participate in lipid liberation from the adipocyte
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