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

Evi Goulielmaki, Anna Ioannidou, Maria Tsekrekou, Kalliopi Stratigi, Ioanna K. Poutakidou, Katerina Gkirtzimanaki, Michalis Aivaliotis, Konstantinos Evangelou, Pantelis Topalis, Janine Altmüller, Vassilis G. Gorgoulis, Georgia Chatzinikolaou and George A. Garinis ()
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Evi Goulielmaki: Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas
Anna Ioannidou: Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas
Maria Tsekrekou: Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas
Kalliopi Stratigi: Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas
Ioanna K. Poutakidou: Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas
Katerina Gkirtzimanaki: Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas
Michalis Aivaliotis: Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas
Konstantinos Evangelou: Athens Medical School
Pantelis Topalis: Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas
Janine Altmüller: University of Cologne
Vassilis G. Gorgoulis: Athens Medical School
Georgia Chatzinikolaou: Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas
George A. Garinis: Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-019-13894-9

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