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Title:
Macrophage de novo NAD+ synthesis specifies immune function in aging and inflammation | Nature Immunology
Description:
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. Macrophages alter their metabolism in response to infection. The authors show that resting macrophages generate nicotinamide adenine dinucleotide via de novo synthesis, but activated and aged cells suppress the rate-limiting enzyme quinolinate phosphoribosyltransferase to regulate mitochondrial and immunological functions.
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address:
name:Department of Neurology & Neurological Sciences, Stanford School of Medicine, Stanford, USA
type:PostalAddress
type:Organization
name:Stanford University
address:
name:Stanford Neuroscience Institute, Stanford University, Stanford, USA
type:PostalAddress
type:Organization
name:Stanford University
address:
name:Stanford Immunology Program, Stanford University, Stanford, USA
type:PostalAddress
type:Organization
email:[email protected]
PostalAddress:
name:Department of Neurology & Neurological Sciences, Stanford School of Medicine, Stanford, USA
name:Neurosciences Graduate Program, Stanford University, Stanford, USA
name:Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, USA
name:Department of Chemistry, Princeton University, Princeton, USA
name:Department of Neurology & Neurological Sciences, Stanford School of Medicine, Stanford, USA
name:Department of Chemical and Systems Biology, Stanford University, Stanford, USA
name:Department of Hematology, Stanford School of Medicine, Stanford, USA
name:Department of Neurology & Neurological Sciences, Stanford School of Medicine, Stanford, USA
name:Department of Genetics, Stanford School of Medicine, Stanford, USA
name:Department of Neurology & Neurological Sciences, Stanford School of Medicine, Stanford, USA
name:Department of Genetics, Stanford School of Medicine, Stanford, USA
name:Department of Pediatrics, Stanford School of Medicine, Stanford, USA
name:Department of Pediatrics, Stanford School of Medicine, Stanford, USA
name:Department of Genetics, Stanford School of Medicine, Stanford, USA
name:Mitchell Cancer Institute, University of South Alabama, Mobile, USA
name:Department of Hematology, Stanford School of Medicine, Stanford, USA
name:Department of Chemical and Systems Biology, Stanford University, Stanford, USA
name:Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, USA
name:Department of Chemistry, Princeton University, Princeton, USA
name:Department of Neurology & Neurological Sciences, Stanford School of Medicine, Stanford, USA
name:Stanford Neuroscience Institute, Stanford University, Stanford, USA
name:Stanford Immunology Program, Stanford University, Stanford, USA
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