Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 16, Pages -Publisher
MDPI
DOI: 10.3390/ijms22168438
Keywords
extracellular vesicles; lipid metabolism; mitochondria-associated ER membranes; alcohol; neuroinflammation; microglia; sphingomyelinases; phospholipids
Funding
- Spanish Ministry of Health, Consumption and Social Welfare-PNSD [2018-I003, 2019-I039]
- Carlos III Institute [RD16/0017/0004]
- FEDER funds (RTA-Network) [RD16/0017/0004]
- FEDER Funds, GVA
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Recent evidence suggests that ethanol-induced EV secretion is closely related to MAMs and SMase activity. Ethanol increases EV release and inflammatory molecule concentration, while also altering lipid metabolism in microglia cells. Inhibiting SMase or MAM activity effectively prevents ethanol-induced increase in EV secretion.
Recent evidence pinpoints extracellular vesicles (EVs) as key players in intercellular communication. Given the importance of cholesterol and sphingomyelin in EV biology, and the relevance of mitochondria-associated endoplasmic reticulum membranes (MAMs) in cholesterol/sphingomyelin homeostasis, we evaluated if MAMs and sphingomyelinases (SMases) could participate in ethanol-induced EV release. EVs were isolated from the extracellular medium of BV2 microglia treated or not with ethanol (50 and 100 mM). Radioactive metabolic tracers combined with thin layer chromatography were used as quantitative methods to assay phospholipid transfer, SMase activity and cholesterol uptake/esterification. Inhibitors of SMase (desipramine and GW4869) and MAM (cyclosporin A) activities were also utilized. Our data show that ethanol increases the secretion and inflammatory molecule concentration of EVs. Ethanol also upregulates MAM activity and alters lipid metabolism by increasing cholesterol uptake, cholesterol esterification and SMase activity in microglia. Notably, the inhibition of either SMase or MAM activity prevented the ethanol-induced increase in EV secretion. Collectively, these results strongly support a lipid-driven mechanism, specifically via SMases and MAM, to explain the effect of ethanol on EV secretion in glial cells.
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