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Inflammatory macrophage dependence on NAD + salvage is a consequence of reactive oxygen species-mediated DNA damage
Ist Teil von
Nature immunology, 2019-04, Vol.20 (4), p.420
Ort / Verlag
United States
Erscheinungsjahr
2019
Quelle
MEDLINE
Beschreibungen/Notizen
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.