folder

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

Authors

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

Journal

  • Nature Communications

Citation

  • Nat Commun 11 (1): 42

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.


DOI

doi:10.1038/s41467-019-13894-9