Inflammatory macrophage dependence on NAD + salvage is a consequence of reactive oxygen species–mediated DNA damage

Alanna M. Cameron, Angela Castoldi, David E. Sanin, Lea J. Flachsmann, Cameron S. Field, Daniel J. Puleston, Ryan L. Kyle, Annette E. Patterson, Fabian Hässler, Joerg M. Buescher, Beth Kelly, Erika L. Pearce, Edward J. Pearce

Research output: Contribution to journalArticlepeer-review

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 languageEnglish (US)
Pages (from-to)420-432
Number of pages13
JournalNature Immunology
Volume20
Issue number4
DOIs
StatePublished - Apr 1 2019
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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