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.