IFNγ regulates NAD+ metabolism to promote the respiratory burst in human monocytes

Blood Advances(2022)

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摘要
Interferon y (IFNy) is an essential and pleiotropic activator of human monocytes, but little is known about the changes in cellular metabolism required for IFNy-induced activation. We sought to elucidate the mechanisms by which IFNy reprograms monocyte metabolism to support its immunologic activities. We found that IFNy increased oxygen consumption rates (OCR) in monocytes, indicative of reactive oxygen species generation by both mitochondria and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Transcriptional profiling revealed that this oxidative phenotype was driven by IFNy-induced reprogramming of NAD+ metabolism, which is dependent on nicotinamide phosphoribosyltransferase (NAMPT)-mediated NAD+ salvage to generate NADH and NADPH for oxidation by mitochondrial complex I and NADPH oxidase, respectively. Consistent with this pathway, monocytes from patients with gain-of-function mutations in STAT1 demonstrated higher-than-normal OCR, whereas chemical or genetic disruption of mitochondrial complex I (rotenone treatment or Leigh syndrome patient monocytes) or NADPH oxidase (diphenyleneiodonium treatment or chronic granulomatous disease [CGD] patient monocytes) reduced OCR. Interestingly, inhibition of NAMPT in healthy monocytes completely abrogated the IFNy-induced oxygen consumption, comparable to levels observed in CGD monocytes. These data identify an IFNy-induced, NAMPT-dependent, NAD+ salvage pathway that is critical for IFNy activation of human monocytes.
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关键词
human monocytes,respiratory burst,metabolism,nad+
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