Study summary · research use only
Macrophage de novo NAD(+) synthesis specifies immune function in aging and inflammation
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
In a cell-based study using macrophages (species not specified), the authors report that de novo NAD+ synthesis via the kynurenine pathway (KP) regulated macrophage immune function. Isotope tracing showed macrophage NAD+ derived substantially from KP metabolism of tryptophan. Blocking de novo NAD+ synthesis depleted NAD+, suppressed mitochondrial NAD+-dependent signaling and respiration, and impaired phagocytosis and resolution of inflammation. Immune challenge activated upstream KP but suppressed NAD+ synthesis by limiting conversion of quinolinate to NAD+, a pattern also seen in aged macrophages. Restoring de novo NAD+ generation in challenged or aged macrophages restored oxidative phosphorylation and baseline immune responses.
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.
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