Tissue-infiltrating macrophages mediate an exosome-based metabolic reprogramming upon DNA damage

Goulielmaki, E.; Ioannidou, A.; Tsekrekou, M.; Stratigi, K.; Poutakidou, I.K.; Gkirtzimanaki, K.; Aivaliotis, M.; Evangelou, K.; Topalis, P.; Altmüller, J.; Gorgoulis, V.G.; Chatzinikolaou, G.; Garinis, G.A.

Tissue-infiltrating macrophages mediate an exosome-based metabolic reprogramming upon DNA damage

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Item Type:	Article
Title:	Tissue-infiltrating macrophages mediate an exosome-based metabolic reprogramming upon DNA damage
Creators Name:	Goulielmaki, E., Ioannidou, A., Tsekrekou, M., Stratigi, K., Poutakidou, I.K., Gkirtzimanaki, K., Aivaliotis, M., Evangelou, K., Topalis, P., Altmüller, J., Gorgoulis, V.G., Chatzinikolaou, G. and Garinis, G.A.
Abstract:	DNA damage and metabolic disorders are intimately linked with premature disease onset but the underlying mechanisms remain poorly understood. Here, we show that persistent DNA damage accumulation in tissue-infiltrating macrophages carrying an ERCC1-XPF DNA repair defect (Er1(F/-)) triggers Golgi dispersal, dilation of endoplasmic reticulum, autophagy and exosome biogenesis leading to the secretion of extracellular vesicles (EVs) in vivo and ex vivo. Macrophage-derived EVs accumulate in Er1(F/-) animal sera and are secreted in macrophage media after DNA damage. The Er1(F/-) EV cargo is taken up by recipient cells leading to an increase in insulin-independent glucose transporter levels, enhanced cellular glucose uptake, higher cellular oxygen consumption rate and greater tolerance to glucose challenge in mice. We find that high glucose in EV-targeted cells triggers pro-inflammatory stimuli via mTOR activation. This, in turn, establishes chronic inflammation and tissue pathology in mice with important ramifications for DNA repair-deficient, progeroid syndromes and aging.
Keywords:	DNA Damage, DNA Repair, DNA-Binding Proteins, Endonucleases, Exosomes, Gene Expression Regulation, Glucose, Glucose Transporter Type 1, Inflammation, Macrophages, Neuropeptides, rab GTP-Binding Proteins, rac1 GTP-Binding Protein, TOR Serine-Threonine Kinases, Transgenic Mice, Animals, Mice
Source:	Nature Communications
ISSN:	2041-1723
Publisher:	Nature Publishing Group
Volume:	11
Number:	1
Page Range:	42
Date:	2 January 2020
Official Publication:	https://doi.org/10.1038/s41467-019-13894-9
PubMed:	View item in PubMed

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