Abstract
ABSTRACTMonocyte-derived cells use an extracellular, acidic, lytic compartment (a lysosomal synapse) for initial degradation of large objects or species bound to the extracellular matrix. Akin to osteoclast degradation of bone, extracellular catabolism is used by macrophages to degrade aggregates of low density lipoprotein (LDL) similar to those encountered during atherogenesis. However, unlike osteoclast catabolism, the lysosomal synapse is a highly dynamic and intricate structure. In this study, we use high resolution three dimensional imaging to visualize compartments formed by macrophages to catabolize aggregated LDL. We show that these compartments are topologically complex, have a convoluted structure and contain sub-regions that are acidified. These sub-regions are characterized by a close apposition of the macrophage plasma membrane and aggregates of LDL that are still connected to the extracellular space. Compartment formation is dependent on local actin polymerization. However, once formed, compartments are able to maintain a pH gradient when actin is depolymerized. These observations explain how compartments are able to maintain a proton gradient while remaining outside the boundaries of the plasma membrane.
Highlights
Our laboratory and others have described a process in which large moieties or species tightly bound to the extracellular matrix are initially digested in an extracellular, acidic, lytic compartment (Zhang et al, 1997; Grosheva et al, 2009; Haka et al, 2009)
AgLDL is sequestered in acidic compartments that are surface-connected We have previously shown that when macrophages interact with aggregated low density lipoproteins (agLDL), regions of low pH are observed at contact sites (Haka et al, 2009)
We have recently shown that in addition to osteoclasts, other monocytederived cells, such as macrophages and monocyte-derived dendritic cells, form an extracellular, acidic, lytic compartment to digest objects that cannot be internalized by standard endocytic mechanisms (Grosheva et al, 2009; Haka et al, 2009, 2015)
Summary
Our laboratory and others have described a process in which large moieties or species tightly bound to the extracellular matrix are initially digested in an extracellular, acidic, lytic compartment (Zhang et al, 1997; Grosheva et al, 2009; Haka et al, 2009) Exophagic catabolism of agLDL results in uptake of cholesterol by the macrophage, leading to foam cell formation, a hallmark of early atherogenesis This degradative mechanism, used by macrophages to allow lysosomal hydrolases to digest large objects, somewhat parallels the Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA.
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