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

Nat Commun. 2020 Jan 2;11(1):42. doi: 10.1038/s41467-019-13894-9.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DNA Damage / physiology*
  • DNA Repair
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Endonucleases / genetics
  • Endonucleases / metabolism
  • Exosomes / metabolism*
  • Exosomes / pathology
  • Gene Expression Regulation
  • Glucose / metabolism
  • Glucose Transporter Type 1 / metabolism
  • Inflammation / genetics
  • Inflammation / metabolism
  • Inflammation / pathology
  • Macrophages / cytology*
  • Macrophages / metabolism
  • Male
  • Mice, Transgenic
  • Neuropeptides / genetics
  • Neuropeptides / metabolism
  • TOR Serine-Threonine Kinases / metabolism
  • rab GTP-Binding Proteins / genetics
  • rab GTP-Binding Proteins / metabolism
  • rac1 GTP-Binding Protein / genetics
  • rac1 GTP-Binding Protein / metabolism

Substances

  • DNA-Binding Proteins
  • Glucose Transporter Type 1
  • Neuropeptides
  • Rac1 protein, mouse
  • Slc2a1 protein, mouse
  • xeroderma pigmentosum group F protein
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Endonucleases
  • Ercc1 protein, mouse
  • Rab10 protein, mouse
  • rab GTP-Binding Proteins
  • rac1 GTP-Binding Protein
  • Glucose