The immune cells known as macrophages roam our tissues in search of debris and malfunctioning cells to engulf and break down. When they encounter something that they cannot handle, however, they start to become a part of the problem that they are attempting to solve. This is perhaps most apparent in the development of atherosclerosis, when macrophages attempt to sweep up damaged lipids and in the process become foam cells, packed so full of fats and cholesterols that they cannot function properly. The plaques that form in blood vessels walls as a part of the progression of atherosclerosis are in large part comprised of foam cells, the remains of previous foam cells, and the lipids that they tried and failed to clean up.


How is it that a macrophage can get itself into this state, taking in so much waste and debris that it simply falls apart? The paper here examines that question, albeit with a focus on how macrophages engulf fat cells elsewhere in the body. The end result is much the same, in the sense that the macrophage becomes bloated by lipids and in consequence becomes a harmful foam cell. This transformation only adds to any ongoing problems in the tissue that required the presence of a macrophage in the first place.



Macrophage interactions with adipocytes are important both in states of metabolic dysfunction and in healthy adipose tissue expansion and remodeling. Despite this importance, our understanding of macrophage-adipocyte interactions is incomplete. It is known that adipose tissue macrophages transform into foam cells and drive the inflammatory changes that occur in adipose tissue, and it appears that macrophages play a protective role in adipose homeostasis, but mount a maladaptive immune response in the setting of obesity. In the setting of obesity, it has been proposed that hypertrophic adipocytes release triglycerides and nonesterified fatty acids that the macrophage can then passively internalize using standard endocytic mechanisms. However, in this study, we show that, rather than endocytosis of released lipids, the macrophages themselves actively participate in lipid liberation from the adipocyte.



Our laboratory and others have described a process in which large moieties or species tightly bound to the extracellular matrix are initially digested by macrophages in an extracellular acidic lytic compartment. We describe this process as exophagy. We have studied exophagy in the context of macrophage degradation of aggregated low-density lipoprotein (LDL), as occurs during atherogenesis. Exophagic catabolism of aggregated LDL results in uptake of cholesterol by the macrophage, leading to foam cell formation. While foam cell formation has been an area of extensive study in the atherosclerosis field, macrophage foam cell formation in adipose tissue has only been reported recently. Given the similarities between these two systems, we examined whether exophagy could be responsible for macrophage degradation of dead adipocytes. This would allow extracellular catabolism and subsequent uptake of pieces of the adipocyte, facilitating macrophage foam cell formation as a consequence of clearing dead adipocytes. 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, as has been demonstrated in the setting of atherosclerosis, leading to a maladaptive inflammatory response. This biology may have particular relevance during clearance of dramatically enlarged adipocytes, as occurs in the setting of obesity.



Here, we demonstrate that adipose tissue macrophages form an extracellular acidic hydrolytic compartment containing lysosomal enzymes delivered via exocytosis. Initial catabolism of the dead adipocyte occurs in these extracellular compartments, allowing the macrophage to internalize pieces of the adipocyte and transform it into a foam cell. We show that macrophage foam cell formation is specific to interaction with dead or dying adipocytes and is blocked when exophagy is inhibited.


Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878183/



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