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

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.

Age‐ and disease‐specific changes of the kynurenine pathway in Parkinson’s and Alzheimer’s disease

“…Apart from KA, changes in Kyn pathway metabolite levels therefore seem to constitute a physiological phenotype of aging in PD and AD and are not part of an ‘accelerated aging‐phenotype’ that is thought to contribute to neurodegeneration (Wyss‐Coray ). Studying the role of the Kyn pathway as a biomarker of (brain) aging, preferably in a longitudinal setting, and deciphering the cell‐specific age‐related changes of Kyn pathway activity in the brain [as previously performed in macrophages (Minhas et al )] could be interesting directions for future research.…”

The impact of PARPs and ADP-ribosylation on inflammation and host–pathogen interactions

“…Hence, NAD ± is consumed by PARPs, and the activity of PARPs depends on the availability of NAD ± (Gupte et al 2017). A recent report indicates that cellautonomous production of NAD ± via the kynurenine pathway (KP) is required to induce normal inflammatory macrophage activation and that the de novo NAD ± synthesis can be impaired in aged macrophages (Minhas et al 2019). Another study proposed a mechanism linking the NAD ± salvage pathway to LPS-induced PARP1 consumption of NAD ± (Cameron et al 2019).…”

Central metabolic interactions of immune cells and microbes: prospects for defeating infections

“…Finally, excessive mROS may lead to irreversible mitochondria damage resulting in the release of DNA, which can lead to NLRP3 and cGAS/STINGmediated inflammation [38][39][40][41]. LPS treatment has also recently been shown to cause depletion of NAD + due to increased activity of NAD-consuming pathways, such poly(ADP-ribose) biosynthesis by PARPs and sirtuins, and downregulation of the NAD biosynthesis gene QPRT, despite upregulation of the initial enzyme IDO1 [42]. Loss of cellular NAD + and mitochondrial deacetylase activity of SIRT3 results in the acetylation and inhibition of complex I, thereby reducing oxidative phosphorylation, and triggering increased proinflammatory responses in macrophages and mice challenged with LPS [42].…”

“…LPS treatment has also recently been shown to cause depletion of NAD + due to increased activity of NAD-consuming pathways, such poly(ADP-ribose) biosynthesis by PARPs and sirtuins, and downregulation of the NAD biosynthesis gene QPRT, despite upregulation of the initial enzyme IDO1 [42]. Loss of cellular NAD + and mitochondrial deacetylase activity of SIRT3 results in the acetylation and inhibition of complex I, thereby reducing oxidative phosphorylation, and triggering increased proinflammatory responses in macrophages and mice challenged with LPS [42]. We note that many of the studies that we discussed used LPS stimulation as a proxy for bacterial infection, with validation with whole bacteria rarely performed.…”

“…Metformin treatment is associated with reduced risk of developing sepsis in humans [118]; however, studies in mice suggest that it may increase opportunistic fungal infections by lowering immune responses to C. albicans and causing hypoglycaemia [43,44]. LPS triggers loss of NAD + , and restoring NAD levels by administration of the precursor metabolite, b-nicotinamide mononucleotide (NMN), prevents inflammatory responses in macrophages after LPS challenge [42]. Interestingly, macrophages show increased inflammatory responses in the elderly, which are known to have altered NAD homeostasis.…”