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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. and Ioannidou, A. and Tsekrekou, M. and Stratigi, K. and Poutakidou, I.K. and Gkirtzimanaki, K. and Aivaliotis, M. and Evangelou, K. and Topalis, P. and Altmüller, J. and Gorgoulis, V.G. and 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
Publisher:Nature Publishing Group
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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