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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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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:org/10.1038/s41590-019-0336-y.


Cite as: http://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 NADsalvage, 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.