Macrophage de novo NAD+ synthesis specifies immune function in aging and inflammation

Paras S. Minhas, Ling Liu, Peter K. Moon, Amit U. Joshi, Christopher Dove, Siddhita Mhatre, Kevin Contrepois, Qian Wang, Brittany A. Lee, Michael Coronado, Daniel Bernstein, Michael P. Snyder, Marie Migaud, Ravindra Majeti, Daria Mochly-Rosen, Joshua D. Rabinowitz, Katrin I. Andreasson

Research output: Contribution to journalArticlepeer-review

278 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)50-63
Number of pages14
JournalNature Immunology
Issue number1
StatePublished - Jan 1 2019

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology


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