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.
Highlights
DNA damage and metabolic disorders are intimately linked with premature disease onset but the underlying mechanisms remain poorly understood
Crossing the Lysozyme 2 (Lys2)-Cre with Rosa YFP transgenic animals confirmed the specificity of Lys2-driven YFP expression to thioglycolate-elicited peritoneal macrophages (TEMs; Fig. 1a) but not to hepatocytes, the primary pancreatic cells (PPCs; Fig. 1b, c) or the pancreas and the white adipose tissue (WAT) that are infiltrated with MAC1possitve macrophages expressing YFP (Fig. 1d)
We find marked differences in the number of positively stained nuclei for FANCI involved in the repair of DNA ICLs32, RAD51 involved in the repair of DSBs by homologous recombination (HR)[33] and phosphorylated ATM, a central mediator of the DNA damage response (DDR; Fig. 1i for bone marrow-derived macrophages (BMDMs) and Fig. 1j for TEMs)
Summary
DNA damage and metabolic disorders are intimately linked with premature disease onset but the underlying mechanisms remain poorly understood. 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. This, in turn, establishes chronic inflammation and tissue pathology in mice with important ramifications for DNA repair-deficient, progeroid syndromes and aging. For helix-distorting damage, cells employ the nucleotide excision repair (NER) pathway[3,4,5], a highly conserved mechanism that recognizes and removes helical distortions throughout the genome or selectively from the actively transcribed strand of genes[6,7]. Using mice with an engineered ERCC1-XPF defect in tissueinfiltrating macrophages, we provide evidence for a fundamental mechanism by which irreparable DNA damage triggers an exosome-based, metabolic reprogramming that leads to chronic inflammation and tissue pathology in NER progeroid syndromes and likely during aging
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