Exocytosis of macrophage lysosomes leads to digestion of apoptotic adipocytes and foam cell formation
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. 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. Macrophage interactions with adipocytes are important both in states of metabolic dysfunction and in healthy adipose tissue expansion and remodeling (1Hotamisligil G.S. 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C. in contact with macrophages local in free that local actin Biol. PubMed Scopus Google Scholar, A.S. I. E. A.R. Macrophages acidic extracellular hydrolytic to Biol. 20: PubMed Scopus Google Scholar, R. D. extracellular and for a in and localization of a lysosomal at the Biol. PubMed Scopus Google Scholar, G. and function of the in Biol. PubMed Scopus Google Scholar, F. A. and of the J. Biol. 2006; PubMed Scopus Google Scholar). We describe this process as We have studied in the of macrophage degradation of as during I. A.S. C. in contact with macrophages local in free that local actin Biol. PubMed Scopus Google Scholar, A.S. I. E. A.R. Macrophages acidic extracellular hydrolytic to Biol. 20: PubMed Scopus Google Scholar). of in of by the to foam cell formation. foam cell formation has been of in the macrophage foam cell formation in has been H. Pecht T. Shaco-Levy R. Harman-Boehm I. Kirshtein B. Kuperman Y. Chen A. Bluher M. Shai I. Rudich A. Adipose tissue foam cells are present in human obesity.J. Clin. Endocrinol. Metab. 2013; 98: 1173-1181Crossref PubMed Scopus (91) Google Scholar). the between we be for macrophage degradation of dead This extracellular and of of the macrophage foam cell formation as a of dead 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 as has been in the setting of I. 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These that, in CLS macrophages exocytosis. It has been that obesity a of in adipose tissue macrophages A. A. M. a of lipid in adipose tissue macrophages of Metab. 2013; Full Text Full Text PDF PubMed Scopus Google Scholar). In of we the of lysosomal in our We in from mice on the and the in lysosomal The in in CLS macrophages that macrophage is in in a mouse of macrophage interactions with dead adipocytes, we a to of the that are to in In this model, adipocyte death by or is a that is in obese and adipocyte in than of the cells after of J. of adipocyte by J. Metab. PubMed Scopus Google Scholar, G.S. Adipose expression of role in insulin PubMed Scopus Google Scholar). We that the mechanism of adipocyte death in is and of cell such as may play a role in to (12Giordano A. Murano I. Mondini E. Perugini J. Smorlesi A. Severi I. Barazzoni R. Scherer P.E. Cinti S. Obese adipocytes show ultrastructural features of stressed cells and die of pyroptosis.J. 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Deyoung S.M. Bodzin J.L. Saltiel A.R. Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity.Diabetes. 2007; 56: 16-23Crossref PubMed Scopus (768) Google Scholar, 11Shapiro H. Pecht T. Shaco-Levy R. Harman-Boehm I. Kirshtein B. Kuperman Y. Chen A. Bluher M. Shai I. Rudich A. Adipose tissue foam cells are present in human obesity.J. Clin. Endocrinol. Metab. 2013; 98: 1173-1181Crossref PubMed Scopus (91) Google Scholar). with we the formation of lipid in the CLS cell culture We that the of the macrophages to the adipocyte into that be foam cell formation. cells with apoptotic adipocytes for in the or of a of with cells and with to lipid In macrophages with apoptotic adipocytes and a of macrophages The of macrophage for with a in adipocyte we that of macrophages foam cells after with apoptotic a of in cells in the or of with not macrophage of This that the by the is to of is a process to macrophage interaction with dead adipocytes, cells for with apoptotic adipocytes or adipocytes the macrophage with then and with to lipid In macrophages with apoptotic adipocytes, of macrophages of foam cell formation. 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M. a of lipid in adipose tissue macrophages of Metab. 2013; Full Text Full Text PDF PubMed Scopus Google Scholar). of the dead adipocyte in the lysosomal the macrophage to internalize of the adipocyte. the of adipocyte triglycerides not this process may to a large of fatty which can be and in lipid 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 to a maladaptive inflammatory cell formation in the is by The to with macrophage the to the process the enzymes and mechanisms are In our CLS cell culture model, and and to both apoptotic and and adipocytes, that this is a However, it is important to that the in with adipocytes that the in process may adipocytes We have that macrophages form extracellular acidic to that be by standard endocytic We that is a process of cells that in A of this biology is degradation of R. D. extracellular and for a in and localization of a lysosomal at the Biol. PubMed Scopus Google Scholar, G. and function of the in Biol. PubMed Scopus Google Scholar, F. A. and of the J. Biol. 2006; PubMed Scopus Google Scholar). However, are between of and macrophage of is not for and of in the degradation at the of a tissue, CLS macrophage biology is by adipocyte the biology may be to a of macrophage by extracellular release of lysosomal the macrophage is a larger than E. J. A. A. C. T. I. on immune to in 2011; PubMed Google Scholar, M. R. S. E. R. interactions a 2014; PubMed Scopus Google Scholar). However, in the to and the adipocyte is not This between and may to the between and inflammation The process may have for the and of the interaction of macrophages with liberation of adipocyte lipid by CLS macrophages or the macrophage gene expression that obesity and The free fatty acids that be released during of dead adipocytes have been to in macrophage to of and M.T. Favelyukis S. Nguyen A.K. Reichart D. Scott P.A. Jenn A. Liu-Bryan R. Glass C.K. Neels J.G. Olefsky J.M. A subpopulation of macrophages infiltrates hypertrophic adipose tissue and is activated by free fatty acids via Toll-like receptors 2 and 4 and JNK-dependent pathways.J. Biol. Chem. 2007; 282: 35279-35292Abstract Full Text Full Text PDF PubMed Scopus (773) Google Scholar, J. N. of Toll-like and by and fatty Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, D. fatty but not fatty the expression of Toll-like Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). a mechanism of inflammation in which adipocyte death leads to macrophage of in adipocyte death and that of via the can macrophage B. Y. D. M. et lysosomal is essential for of 2014; PubMed Scopus Google Scholar). it is that, to macrophage foam cells in macrophage in is not a of lipid but rather from J.G. N. Reichart D. I. D. et of macrophage lipid and inflammatory Full Text Full Text PDF PubMed Scopus Google Scholar). We have that the extracellular compartments for are A.S. I. E. A.R. Macrophages acidic extracellular hydrolytic to Biol. 20: PubMed Scopus Google Scholar). can be at but they This can release both and lysosomal enzymes into the extracellular which to on understanding the nature of the macrophage-adipocyte mechanisms to and a for of The E. for cells and and for with macrophage crown-like and fat human macrophage fat white adipose tissue white adipose tissue inflammation