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Nat Commun. 2020 Jan 2;11(1):42. doi: 10.1038/s41467-019-13894-9.

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

Author information

1
Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, GR70013, Heraklion, Crete, Greece.
2
Department of Biology, University of Crete, Heraklion, Crete, Greece.
3
Department of Histology and Embryology, Athens Medical School, GR11527, Athens, Greece.
4
Cologne Center for Genomics (CCG), Institute for Genetics, University of Cologne, 50931, Cologne, Germany.
5
Biomedical Research Foundation of the Academy of Athens, 4 Soranou Ephessiou St. GR-11527, Athens, Greece.
6
Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Wilmslow Road, Manchester, M20 4QL, UK.
7
Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, GR70013, Heraklion, Crete, Greece. garinis@imbb.forth.gr.
8
Department of Biology, University of Crete, Heraklion, Crete, Greece. garinis@imbb.forth.gr.

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 (Er1F/-) 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 Er1F/- animal sera and are secreted in macrophage media after DNA damage. The Er1F/- 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.

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