Triglyceride breakdown from lipid droplets regulates the inflammatory response in macrophages

Abstract

Significance Lipid droplets (LDs) are ubiquitous organelles that play important roles in cellular energy homeostasis, tightly regulating the accumulation and release of lipids. In macrophages, lipids accumulate in LDs during inflammation. However, it is unclear how inflammatory activation promotes the accumulation of lipids in LDs, and how the dynamic between lipid accumulation and breakdown could drive or inhibit inflammation. Elucidating the role of lipid accumulation during inflammation may provide important knowledge to influence inflammatory processes during health and disease. We identify the importance of the hypoxia-inducible lipid droplet–associated protein and the intracellular adipose triglyceride lipase in the regulation of lipid accumulation and breakdown in inflammatory macrophages. Furthermore, we determine the regulatory effect of lipid breakdown from LDs in supporting inflammation.

Immunolipidomics Reveals a Globoside Network During the Resolution of Pro-Inflammatory Response in Human Macrophages

“…Evidently, the macrophage uses lipid biosynthesis to mount an effective pro-inflammatory response and previous studies show how this crosstalk between lipidomic and immune responses (i.e. immunolipidomics) occur at the level of individual lipids and/or as part of lipid droplets ( 8 , 12 , 13 , 16 , 20 ). A less studied but equally important aspect, is the usage of specific lipids such as sphingolipids by the macrophage to regulate the ongoing TLR4 trafficking and signalling events and the evolution of intracellular pathways that shift from pro-inflammatory (3h-8h) to resolution (8h-24h) phases ( 29 , 30 ).…”

“…These LPS-induced changes in glycolysis and TCA cycle activity coincide with lipid uptake and intracellular lipid droplet formation that are necessary for the storage of triglycerides and cholesteryl esters (CE) (8)(9)(10)(11). Lipid droplets that form in response to LPS are innate immune hubs at the crosstalk of cell metabolism and host defense (12,13). Thus, lipid metabolism is linked, directly or through other central carbon pathways, to the macrophage immune response and its inhibition can modulate the pro-inflammatory (8,14,15) or pro-resolution (16) states of these cells.…”

Recent Advances on the Role of ATGL in Cancer

“…Functionally, elevated FAs content promotes inflammatory responses in macrophages ( 88 ), while high LDs content attenuates them ( 83 ). In HIG-2-deficient bone marrow cells show a decrease in triglyceride content with an enhanced inflammatory response ( 85 ). The pro-inflammatory effect of FAs on inflammation may presumably be due to the fact that elevated intracellular FAs content increases the availability of FAs as precursors of inflammatory mediators, such as prostaglandins.…”

“…Currently, there is growing evidence that lipids have a significant impact on macrophage function and differentiation. The accumulation of triglycerides and LDs can be observed in inflammation-activated macrophages (82)(83)(84)(85)(86). Macrophage activation by Lipopolysaccharides (LPS) was found to inhibit ATGL-mediated triglyceride hydrolysis by upregulating HIG-2 in activated macrophages, ultimately leading to the accumulation of LDs (85).…”

“…The accumulation of triglycerides and LDs can be observed in inflammation-activated macrophages (82)(83)(84)(85)(86). Macrophage activation by Lipopolysaccharides (LPS) was found to inhibit ATGL-mediated triglyceride hydrolysis by upregulating HIG-2 in activated macrophages, ultimately leading to the accumulation of LDs (85). In contrast, upregulation of HIG-2 expression (31) and accumulation of LDs (87) was also found in TAMs.…”