Macrophage de novo NAD synthesis specifies immune function in aging and inflammation. Author Paras Minhas, Ling Liu, Peter Moon, Amit Joshi, Christopher Dove, Siddhita Mhatre, Kevin Contrepois, Qian Wang, Brittany Lee, Michael Coronado, Daniel Bernstein, Michael Snyder, Marie Migaud, Ravindra Majeti, Daria Mochly-Rosen, Joshua Rabinowitz, Katrin Andreasson Publication Year 2019 Type Journal Article Abstract 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. 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 Journal Nat Immunol Volume 20 Issue 1 Pages 50-63 Date Published 01/2019 ISSN Number 1529-2916 DOI 10.1038/s41590-018-0255-3 Alternate Journal Nat. Immunol. PMID 30478397 PubMedGoogle ScholarBibTeXEndNote X3 XML