TY - JOUR
TI - Tissue-infiltrating macrophages mediate an exosome-based metabolic
reprogramming upon DNA damage
AU - Goulielmaki, Evi
AU - Ioannidou, Anna
AU - Tsekrekou, Maria
AU - Stratigi,
AU - Kalliopi
AU - Poutakidou, Ioanna K.
AU - Gkirtzimanaki, Katerina and
AU - Aivaliotis, Michalis
AU - Evangelou, Konstantinos
AU - Topalis, Pantelis
AU - and Altmueller, Janine
AU - Gorgoulis, Vassilis G.
AU - Chatzinikolaou,
AU - Georgia
AU - Garinis, George A.
JO - Nature Communications
PY - 2020
VL - 11
TODO - 1
SP - null
PB - Nature Publishing Group
SN - 2041-1723
TODO - 10.1038/s41467-019-13894-9
TODO - null
TODO - 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.
ER -