| First Author | Minhas PS | Year | 2019 |
| Journal | Nat Immunol | Volume | 20 |
| Issue | 1 | Pages | 50-63 |
| PubMed ID | 30478397 | Mgi Jnum | J:282516 |
| Mgi Id | MGI:6381134 | Doi | 10.1038/s41590-018-0255-3 |
| Citation | Minhas PS, et al. (2019) Macrophage de novo NAD(+) synthesis specifies immune function in aging and inflammation. Nat Immunol 20(1):50-63 |
| abstractText | Recent advances highlight a pivotal role for cellular metabolism in programming immune responses. Here, we demonstrate that cell-autonomous generation of nicotinamide adenine dinucleotide (NAD(+)) via the kynurenine pathway (KP) regulates macrophage immune function in aging and inflammation. Isotope tracer studies revealed that macrophage NAD(+) derives substantially from KP metabolism of tryptophan. Genetic or pharmacological blockade of de novo NAD(+) synthesis depleted NAD(+), suppressed mitochondrial NAD(+)-dependent signaling and respiration, and impaired phagocytosis and resolution of inflammation. Innate immune challenge triggered upstream KP activation but paradoxically suppressed cell-autonomous NAD(+) synthesis by limiting the conversion of downstream quinolinate to NAD(+), a profile recapitulated in aging macrophages. Increasing de novo NAD(+) generation in immune-challenged or aged macrophages restored oxidative phosphorylation and homeostatic immune responses. Thus, KP-derived NAD(+) operates as a metabolic switch to specify macrophage effector responses. Breakdown of de novo NAD(+) synthesis may underlie declining NAD(+) levels and rising innate immune dysfunction in aging and age-associated diseases. |
