NAD+激酶
炎症
烟酰胺腺嘌呤二核苷酸
巨噬细胞
免疫系统
犬尿氨酸途径
生物
犬尿氨酸
细胞生物学
先天免疫系统
免疫学
生物化学
酶
色氨酸
体外
氨基酸
作者
Paras S. Minhas,Ling Liu,Peter C. Moon,Amit Joshi,Christopher Dove,Siddhita D. Mhatre,Kévin Contrepois,Qian Wang,Brittany Lee,Michael Coronado,Daniel Bernstein,Xin Li,Marie E. Migaud,Ravindra Majeti,Daria Mochly-Rosen,Joshua D. Rabinowitz,Katrin I. Andreasson
标识
DOI:10.1038/s41590-018-0255-3
摘要
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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