Preprint Extracellular vesicles promote autophagy in human microglia through lipid raft-dependent mechanisms, 2023, Romenskaja et al.

Extracellular vesicles promote autophagy in human microglia through lipid raft-dependent mechanisms
Diana Romenskaja; Ugne Jonavice; Augustas Pivoriunas

Autophagy dysfunction has been closely related with pathogenesis of many neurodegenerative diseases and therefore represents a potential therapeutic target. Extracellular vesicles (EVs) may act as a potent anti-inflammatory agents and also modulators of autophagy in target cells. However, the molecular mechanisms by which EVs modulate autophagy flux in human microglia remain largely unexplored.

In the present study we investigated the effects of EVs derived from human oral mucosa stem cells on the autophagy in human microglia. We demonstrate that EVs promoted autophagy and autophagic flux in human microglia and that this process was dependent on the integrity of lipid rafts. LPS also activated autophagy, but combined treatment with EVs and LPS suppressed autophagy response indicating interference between these signalling pathways.

Blockage of Toll-like receptor 4 (TLR4) with anti-TLR4 antibody suppressed EV-induced autophagy. Furthermore, blockage of EV associated HSP70 chaperone which is one of the endogenous ligands of the TLR4 also suppressed EV induced lipid raft formation and autophagy. Pre-treatment of microglia with selective inhibitor of αvβ3/αvβ5 integrins cilengitide inhibited EV-induced autophagy.

Finally, blockage of purinergic P2X4 receptor (P2X4R) with selective inhibitor 5-BDBD also suppressed of EV-induced autophagy. In conclusion, we demonstrate that EVs activate autophagy in human microglia through interaction with HSP70/TLR4, αVβ3/αVβ5, and P2X4R signalling pathways and that these effects depend on the integrity of lipid rafts.

Our findings could be used for development of new therapeutic strategies targeting disease-associated microglia.

Link | PDF (Preprint: BioRxiv)

 

I've had good and bad responses to specific fatty acids. I haven't bothered to try to figure out the mechanisms involved, because as this paper shows, there are just too many possibilities, many unexplored. If all PWME showed the same sort of response to a specific fatty acid or other factor, then it would be worth exploring. If just a few people show the response, and some others show the opposite response, well, that's individual variations.

 

Simplifying—EVs are a thing in MECFS. Autophagy is apparently impaired in MECFS. So if we have abundant EVs why is our autophagy impaired—bad lipid rafts?

e.g.

https://www.s4me.info/threads/cytok...oteaux-levine-hanson-et-al.17242/#post-294074

https://www.s4me.info/threads/circu...arkers-in-cfs-2018-castro-marrero-et-al.3214/