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.

Metabolically Activated Adipose Tissue Macrophages Perform Detrimental and Beneficial Functions during Diet-Induced Obesity

“…Previous studies showed that lysosomal exocytosis by macrophages is required for them to clear dead adipocytes (Haka et al, 2016). Since macrophages (~20µm diameter) are much smaller than adipocytes (~120µm diameter), they cannot clear dead adipocytes through a traditional phagocytosis mechanism.…”

“…To this end, we used a more physiologically relevant co-culture assay (Haka et al, 2016) that quantifies i ) the delivery of lysosomal contents from macrophages to apoptotic 3T3-L1 adipocytes, and ii ) the subsequent accumulation of adipocyte-derived lipids in the macrophage (Fig. 2B).…”

“…First, because adipocytes are so large, macrophages cannot phagocytose them. Instead, their clearance relies on the formation of extracellular lysosomal compartments between many macrophages and one adipocyte (Haka et al, 2016), resulting in the formation of crown-like structures. Second, adipocytes are predominantly comprised of triglycerides.…”

“…Macrophage clearance of apoptotic adipocytes and subsequent accumulation of lipids were performed as previously described (Haka et al, 2016). See supplemental methods for additional details.…”

Progranulin in the hematopoietic compartment protects mice from atherosclerosis

“…Exophagy refers to a process in which large macromolecular substrates (such as aggregated LDL (agLDL) and dead/dying adipocytes) are degraded in a plasma membrane-bound extracellular compartment by extruded lysosomal contents (35–38). The degraded proteins and lipids are subsequently taken up into cells via endocytosis.…”