Abstract
The adoption of Warburg metabolism is critical for the activation of macrophages in response to lipopolysaccharide. Macrophages stimulated with lipopolysaccharide increase their expression of nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme in NAD + salvage, and loss of NAMPT activity alters their inflammatory potential. However, the events that lead to the cells' becoming dependent on NAD + salvage remain poorly defined. We found that depletion of NAD + and increased expression of NAMPT occurred rapidly after inflammatory activation and coincided with DNA damage caused by reactive oxygen species (ROS). ROS produced by complex III of the mitochondrial electron-transport chain were required for macrophage activation. DNA damage was associated with activation of poly(ADP-ribose) polymerase, which led to consumption of NAD + . In this setting, increased NAMPT expression allowed the maintenance of NAD + pools sufficient for glyceraldehyde-3-phosphate dehydrogenase activity and Warburg metabolism. Our findings provide an integrated explanation for the dependence of inflammatory macrophages on the NAD + salvage pathway.
Original language | English (US) |
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Pages (from-to) | 420-432 |
Number of pages | 13 |
Journal | Nature Immunology |
Volume | 20 |
Issue number | 4 |
DOIs | |
State | Published - Apr 1 2019 |
Externally published | Yes |
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology