期刊
NATURE IMMUNOLOGY
卷 20, 期 4, 页码 420-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41590-019-0336-y
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资金
- National Institutes of Health [AI 110481, CA18125]
- Capes Humboldt Research Fellowship
- Sir Henry Wellcome Fellowship - Wellcome Trust
- Max Planck Society
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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