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

TitleMacrophage de novo NAD synthesis specifies immune function in aging and inflammation.
Publication TypeJournal Article
Year of Publication2019
AuthorsMinhas, 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
JournalNat Immunol
Volume20
Issue1
Pagination50-63
Date Published2019 01
ISSN1529-2916
KeywordsAging, 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

<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>

DOI10.1038/s41590-018-0255-3
Alternate JournalNat. Immunol.
PubMed ID30478397
PubMed Central IDPMC6768398
Grant ListDP1 DK113643 / DK / NIDDK NIH HHS / United States
R01 CA188055 / CA / NCI NIH HHS / United States
RF1 AG058047 / AG / NIA NIH HHS / United States
1P50 AG047366 / NH / NIH HHS / United States
R37 AA11147 / NH / NIH HHS / United States
T32 HL094274 / HL / NHLBI NIH HHS / United States
P50 AG047366 / AG / NIA NIH HHS / United States
K12 HL120001 / HL / NHLBI NIH HHS / United States
R00 HL129474 / HL / NHLBI NIH HHS / United States
R37 AA011147 / AA / NIAAA NIH HHS / United States
5R01CA188055 / NH / NIH HHS / United States
5U54DK10255603 / NH / NIH HHS / United States
RO1AG048232 / NH / NIH HHS / United States
5T32HL094274 / NH / NIH HHS / United States
1S10RR02678001 / NH / NIH HHS / United States
P30 CA124435 / CA / NCI NIH HHS / United States
R01 AG048232 / AG / NIA NIH HHS / United States
K99 HL129474 / HL / NHLBI NIH HHS / United States
RF1AG058047 / NH / NIH HHS / United States