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

Author

Listed:
  • 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
    University of Crete)

  • Maria Tsekrekou

    (Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas
    University of Crete)

  • 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
    Biomedical Research Foundation of the Academy of Athens
    University of Manchester, Manchester Academic Health Science Centre)

  • 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
    University of Crete)

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.

Suggested Citation

  • Evi Goulielmaki & Anna Ioannidou & Maria Tsekrekou & Kalliopi Stratigi & Ioanna K. Poutakidou & Katerina Gkirtzimanaki & Michalis Aivaliotis & Konstantinos Evangelou & Pantelis Topalis & Janine Altmül, 2020. "Tissue-infiltrating macrophages mediate an exosome-based metabolic reprogramming upon DNA damage," Nature Communications, Nature, vol. 11(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-13894-9
    DOI: 10.1038/s41467-019-13894-9
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    Cited by:

    1. Athanasios Siametis & Kalliopi Stratigi & Despoina Giamaki & Georgia Chatzinikolaou & Alexia Akalestou-Clocher & Evi Goulielmaki & Brian Luke & Björn Schumacher & George A. Garinis, 2024. "Transcription stress at telomeres leads to cytosolic DNA release and paracrine senescence," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

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