Macrophage de novo NAD+ synthesis specifies immune function in aging and inflammation.
Nat Immunol
; 20(1): 50-63, 2019 01.
Article
em En
| MEDLINE
| ID: mdl-30478397
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Envelhecimento
/
Indolamina-Pirrol 2,3,-Dioxigenase
/
Inflamação
/
Macrófagos
/
Mitocôndrias
/
NAD
Limite:
Animals
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article