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

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.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0004-A60E-2 Version Permalink: http://hdl.handle.net/21.11116/0000-0004-DBCA-2
Genre: Journal Article

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 Creators:
Cameron, Alanna M.1, Author
Castoldi, Angela1, Author
Sanin, David E.1, Author
Flachsmann, Lea J.1, Author
Field, Cameron S.1, Author
Puleston, Daniel J.1, Author
Kyle, Ryan L.1, Author
Patterson, Annette1, Author
Hassler, Fabian1, Author
Buescher, Joerg M.1, Author
Kelly, Beth1, Author
Pearce, Erika Laine1, Author              
Pearce, Edward Jonathen1, Author              
Affiliations:
1Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society, 79108 Freiburg, DE, ou_2243640              

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 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.

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Language(s): eng - English
 Dates: 2019-04
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: org/10.1038/s41590-019-0336-y
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Title: Nature Immunology
  Other : Nat. Immunol.
Source Genre: Journal
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Publ. Info: New York, NY : Nature America Inc.
Pages: - Volume / Issue: 20 Sequence Number: - Start / End Page: 420 - 432 Identifier: ISSN: 1529-2908
CoNE: https://pure.mpg.de/cone/journals/resource/974392607073