IFNg Regulates NAD+ Metabolism in Human Monocytes
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA736708 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14779224_1.fastq.gz | Fastqsanger.gz | |||
| SRR14779224_2.fastq.gz | Fastqsanger.gz | |||
| SRR14779225_1.fastq.gz | Fastqsanger.gz | |||
| SRR14779225_2.fastq.gz | Fastqsanger.gz | |||
| SRR14779226_1.fastq.gz | Fastqsanger.gz |
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Project description:IFNg is an essential and pleiotropic activator of monocytes, but little is known about the changes in cellular metabolism required for IFNg-induced activation. We sought to characterize and elucidate the mechanisms by which IFNg reprograms monocyte metabolism to support its immunologic activities. Monocytes from healthy controls and patients with gain-of-function mutations in STAT1 (STAT1 GOF), or loss-of-function mutations in mitochondrial complex I (Leigh syndrome) and NADPH oxidase (chronic granulomatous disease, CGD) were metabolically phenotyped. We found that IFNg increased oxygen consumption rates (OCR), indicative of reactive oxygen species generation by both mitochondria and NADPH oxidase. Transcriptional profiling of human monocyte derived macrophages revealed that this oxidative phenotype was driven by an IFNg-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. Monocytes from patients with STAT1 GOF demonstrated higher than normal OCR, while monocytes from Leigh syndrome and CGD patients demonstrated reduced OCR. Chemical inhibition of NAMPT completely abrogated the IFNg-induced oxygen consumption, comparable to levels observed in CGD patients. These data identify an IFNg-induced, NAMPT-dependent, NAD+ salvage pathway that is critical for IFNg activation of human monocytes.
2021-12-31 | GSE176562 | GEO
Project description:Human peripheral blood monocytes were treated with control or with 25 ng/ml IFNg for 24 hours. RNA was collected, processed and hybridized to Affymetrix HGU133Plus2 chips.
2019-12-28 | GSE142672 | GEO
Project description:Cellular senescence is a stable cell growth arrest that is implicated in tissue aging and cancer. Senescent cells are characterized by an upregulation of proinflammatory and immunosuppressive cytokines and chemokines, which is termed as senescence-associated secretory phenotype (SASP). NAD+ metabolism plays a critical role in both tissue aging and cancer. However, the role of NAD+ metabolism in regulating the SASP is not well understood. Here we show that nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD+ salvage pathway, governs the strengths of proinflammatory SASP during senescence. In contrast to downregulation of NAMPT during replicative senescence, NAMPT is upregulated during oncogene-induced senescence. NAMPT selectively regulates proinflammatory, but not immunosuppressive, SASP. NAMPT is regulated by HMGA1 through a distal enhancer element during senescence. HMGA1/NAMPT/NAD+ signaling axis promotes proinflammatory SASP through enhancing glycolysis and mitochondria respiration. Mechanistically, HMGA1/NAMPT promotes proinflammatory SASP through NAD+-mediated suppression of AMPK kinase, which suppresses p53-mediated inhibition of p38MAPK to enhance NFb activity. SASP regulation by NAD+ metabolism is independent of senescence-associated cell growth arrest. An increase in NAD+ levels is sufficient to convert SASP from low to high levels during replicative senescence. Together, we conclude that NAD+ metabolism governs the strengths of proinflammatory SASP. Given the tumor promoting effects of proinflammatory SASP, our results suggest that anti-ageing dietary NAD+ augmentation should be administered with precision.
2019-03-14 | GSE111841 | GEO
Project description:We did transcriptome profiling for monocytes treated with or without IFNg to characterize IFNg response.
2016-09-12 | GSE84691 | GEO
Project description:We characterized the regulation of 2 histone marks by IFNg in human monocytes
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Project description:NAD+ metabolism governs proinflammatory senescence secretome
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Project description:Mammalian female reproductive lifespan is typically significantly shorter than life expectancy and is associated with a decrease in ovarian NAD levels. However, the mechanisms underlying this loss of ovarian NAD are unclear. Here, we show that CD38, a NAD consuming enzyme, is expressed in the ovarian extrafollicular space, primarily in immune cells, and its levels increase with reproductive age. Reproductively young mice lacking CD38 exhibit larger primordial follicle pools, elevated ovarian NAD levels, and increased fecundity relative to wild type controls. This larger ovarian reserve results from a prolonged window of follicle formation during early development. However, the beneficial effect of CD38 loss on reproductive function is not maintained at advanced age. Our results demonstrate a novel role of CD38 in regulating ovarian NAD metabolism and establishing the ovarian reserve, a critical process that dictates a female reproductive lifespan.
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Project description:Nicotinamide adenine dinucleotide (NAD+) is a critical metabolic co-enzyme which is strongly implicated in the pathogenesis of brain aging and neurodegenerative diseases. Prevention of age-related decline in brain NAD+ levels is an attractive therapeutic strategy for combating age-related neurodegeneration, emphasizing the need to fully understand molecular mechanisms regulating brain NAD+ levels. Previous work has shown that the circadian protein REV-ERBα regulates cellular NAD+ levels in cardiac tissue via control of the NAD+ producing enzyme NAMPT. Whether this pathway regulates brain NAD+ levels, however, is unknown. Here, we show that REV-ERBα controls brain NAD+ levels through a distinct pathway involving suppression of the NAD+ consuming enzyme CD38 in astrocytes. Under basal conditions, REV-ERBα suppresses the transcription factor NFIL3 (E4BP4) which itself provides tonic inhibition of CD38 expression, elevating CD38 levels and keeping NAD+ levels low. Deletion of REV-ERBα, either globally or specifically in astrocytes, led to induction of NFIL3, suppression of CD38, increased NAD+, and mitigated protein aggregation, inflammation, and neurodegeneration in a mouse model of tauopathy. This pathway appears to be unique to the brain, as REV-ERBα deletion does not affect NAMPT expression in the brain, does not suppress CD38 in the liver, and has an opposite effect on NAD+ levels in the brain as in the heart. Our data show that the circadian nuclear receptor REV-ERBα can regulate NAD+ via distinct mechanisms in different tissues and define a REV-ERBα-NFIL3-NAD+ downstream pathway controlling brain NAD+ metabolism and neurodegeneration.
2025-06-27 | GSE255975 | GEO
Project description:Nicotinamide adenine dinucleotide (NAD), a cofactor for hundreds of metabolic reactions in all cell types, plays an essential role in diverse cellular processes including metabolism, DNA repair, and aging. NAD metabolism is critical to maintain cellular homeostasis in response to environmental signals, however, how it is impacted by the environment remains unclear. Here, we report an unexpected trans-kingdom cooperation between bacteria and mammalian cells wherein bacteria contribute to host NAD biosynthesis. Bacteria confer mammalian cells with the resistance to inhibitors of NAMPT, the rate limiting enzyme in the main vertebrate NAD salvage pathway. Mechanistically, a microbial nicotinamidase (PncA) that converts nicotinamide to nicotinic acid, a key precursor in the alternative deamidated NAD salvage pathway, is necessary and sufficient for this protective effect. This bacteria-enabled bypass of the pharmacologically induced metabolic block in mammalian cells represents a novel paradigm in drug resistance. This host-microbe metabolic interaction also dramatically enhances the hepatic NAD-boosting efficiency of nicotinamide and nicotinamide riboside supplementation, demonstrating a crucial role of microbes, gut microbiota in particular, in systemic NAD metabolism.
2020-03-03 | GSE127750 | GEO