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

Nat Immunol. 2019 Jan;20(1):50-63. doi: 10.1038/s41590-018-0255-3. Epub 2018 Nov 26.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / physiology*
  • Animals
  • Cells, Cultured
  • Homeostasis
  • Immunity, Innate
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / genetics
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism*
  • Inflammation / immunology*
  • Kynurenine / metabolism
  • Macrophages / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / metabolism*
  • NAD / metabolism*
  • Oxidative Phosphorylation
  • Pentosyltransferases / genetics
  • Phagocytosis
  • Signal Transduction
  • Tryptophan / metabolism

Substances

  • IDO1 protein, mouse
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • NAD
  • Kynurenine
  • Tryptophan
  • Pentosyltransferases
  • nicotinate-nucleotide diphosphorylase (carboxylating)