@article{2558,
  keywords = {Animals, Cells, Cultured, Signal Transduction, Mice, Aging, Mice, Inbred C57BL, Mitochondria, Homeostasis, NAD, Mice, Knockout, Oxidative Phosphorylation, Immunity, Innate, Inflammation, Indoleamine-Pyrrole 2,3,-Dioxygenase, Kynurenine, Macrophages, Pentosyltransferases, Phagocytosis, Tryptophan},
  author = {Paras Minhas and Ling Liu and Peter Moon and Amit Joshi and Christopher Dove and Siddhita Mhatre and Kevin Contrepois and Qian Wang and Brittany Lee and Michael Coronado and Daniel Bernstein and Michael Snyder and Marie Migaud and Ravindra Majeti and Daria Mochly-Rosen and Joshua Rabinowitz and Katrin Andreasson},
  title = {Macrophage de novo NAD synthesis specifies immune function in aging and inflammation.},
  abstract = {<p>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.</p>
},
  year = {2019},
  journal = {Nat Immunol},
  volume = {20},
  pages = {50-63},
  month = {01/2019},
  issn = {1529-2916},
  doi = {10.1038/s41590-018-0255-3},
  language = {eng},
}