| First Author | Cameron AM | Year | 2019 |
| Journal | Nat Immunol | Volume | 20 |
| Issue | 4 | Pages | 420-432 |
| PubMed ID | 30858618 | Mgi Jnum | J:282383 |
| Mgi Id | MGI:6380768 | Doi | 10.1038/s41590-019-0336-y |
| Citation | Cameron AM, et al. (2019) Inflammatory macrophage dependence on NAD(+) salvage is a consequence of reactive oxygen species-mediated DNA damage. Nat Immunol 20(4):420-432 |
| abstractText | 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. |
