Inflammatory macrophage dependence on NAD+ salvage is a consequence of reactive oxygen species–mediated DNA damage
Open accessAbstract
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.
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NAD+ turnover during the first few hours of M1 macrophage polarization depends on reactive oxygen species-induced DNA damage and PARP1 activation.
“This study and another recent report6,102 suggest that this NAD+ turnover, particularly during the first few hours of macrophage M1 polarization, depends on reactive oxygen species-induced DNA damage and activation of PARP1.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [102]
M1 macrophages are protected from reactive oxygen species-induced DNA damage as a result of increased transcription of antioxidant defence genes such as SOD2.
“M1 macrophages are protected from reactive oxygen species-induced DNA damage as a result of increased transcription of genes involved in antioxidant defence, such as SOD2 (REFS102–104).”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [102]
M1 macrophage polarization is associated with enhanced NAD+ degradation, and inhibiting NAMPT blocks glycolytic shifts in M1 macrophages, limiting proinflammatory responses in vitro and reducing systemic inflammation in vivo in response to sepsis.
“a recent study found that M1 macrophage polarization is associated with enhanced degradation of NAD+ and that inhibiting NAMPT blocks glycolytic shifts in M1 macrophages, limiting proinflammatory responses in vitro and reducing systemic inflammation in vivo in response to sepsis102.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [102]
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NAD+ metabolism and its roles in cellular processes during ageing
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- Authors
- Cameron, A. M., Castoldi, A., Sanin, D. E., Flachsmann, L. J., Field, C. S., Puleston, D. J., Kyle, R. L., Patterson, A. E., Hässler, F., Buescher, J. M., Kelly, B., Pearce, E. L., & Pearce, E. J.
- Affiliations
- Max Planck Institute of Immunobiology and Epigenetics (DE)
- University of Oxford (GB)
- University of Freiburg (DE)
- Corresponding author
- Pearce, Edward J.
- ORCID
- Venue
- Nature Immunology
- Published
- 2019-03-11
- Volume
- 20
- Issue
- 4
- Pages
- 420-432
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC12842115
- OpenAlex
- W2921138669
- Cited by
- 269
- References
- 54
- Citations by year
- 2026: 28 · 2025: 39 · 2024: 38 · 2023: 38 · 2022: 45 · 2021: 38 · 2020: 34 · 2019: 9
- FWCI
- 16.99
- Type
- journal article
- Language
- en
- Open access
- green
- pmc.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion)
- FreiDok plus (Universitätsbibliothek Freiburg) (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Wellcome Trust (201330/Z/16/Z)
- Rheinische Friedrich-Wilhelms-Universität Bonn
- National Institute of Allergy and Infectious Diseases (R01AI110481, R01AI053825)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Keywords
- macrophage activation, NAD+ salvage pathway, visfatin, reactive oxygen species, DNA damage, lipopolysaccharide, mitochondrial complex III, poly(ADP-ribose) polymerase, glyceraldehyde-3-phosphate dehydrogenase, redox homeostasis, inflammation
- MeSH terms
- Acrylamides, Animals, Cells, Cultured, DNA Damage, Humans, Inflammation, Macrophage Activation, Macrophages, Mice, Inbred C57BL, Mitochondria, NAD, Piperidines, Electron Transport Complex III, Cytokines, Reactive Oxygen Species, Mice, Nicotinamide Phosphoribosyltransferase, HEK293 Cells
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