Title | Macrophage de novo NAD+ synthesis specifies immune function in aging and inflammation. |
Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Minhas, PS, Liu, L, Moon, PK, Joshi, AU, Dove, C, Mhatre, S, Contrepois, K, Wang, Q, Lee, BA, Coronado, M, Bernstein, D, Snyder, MP, Migaud, M, Majeti, R, Mochly-Rosen, D, Rabinowitz, JD, Andreasson, KI |
Journal | Nat Immunol |
Volume | 20 |
Issue | 1 |
Pagination | 50-63 |
Date Published | 2019 01 |
ISSN | 1529-2916 |
Keywords | Aging, Animals, Cells, Cultured, Homeostasis, Immunity, Innate, Indoleamine-Pyrrole 2,3,-Dioxygenase, Inflammation, Kynurenine, Macrophages, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitochondria, NAD, Oxidative Phosphorylation, Pentosyltransferases, Phagocytosis, Signal Transduction, Tryptophan |
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. |
DOI | 10.1038/s41590-018-0255-3 |
Alternate Journal | Nat. Immunol. |
PubMed ID | 30478397 |
Grant List | RO1AG048232 / NH / NIH HHS / United States RF1AG058047 / NH / NIH HHS / United States 1P50 AG047366 / NH / NIH HHS / United States 5U54DK10255603 / NH / NIH HHS / United States 5R01CA188055 / NH / NIH HHS / United States R37 AA11147 / NH / NIH HHS / United States 5T32HL094274 / NH / NIH HHS / United States 1S10RR02678001 / NH / NIH HHS / United States |