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

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

doi:10.1038/s41590-019-0336-y

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

MPS-Authors

Cameron, Alanna M.
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Castoldi, Angela
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Sanin, David E.
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Flachsmann, Lea J.
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Field, Cameron S.
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Puleston, Daniel J.
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Kyle, Ryan L.
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Patterson, Annette
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Hassler, Fabian
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Buescher, Joerg M.
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Kelly, Beth
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Pearce, Erika L.
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

/persons/resource/persons201435

Pearce, Edward J.
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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https://www.nature.com/articles/s41590-019-0336-y
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Citation

Cameron, A. M., Castoldi, A., Sanin, D. E., Flachsmann, L. J., Field, C. S., Puleston, D. J., et al. (2019). Inflammatory macrophage dependence on NAD⁺ salvage is a consequence of reactive oxygen species-mediated DNA damage. Nature Immunology, 20, 420-432. doi:10.1038/s41590-019-0336-y.

Cite as: https://hdl.handle.net/21.11116/0000-0004-A60E-2

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.