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Series GSE176562 Query DataSets for GSE176562
Status Public on Dec 31, 2021
Title IFNg Regulates NAD+ Metabolism in Human Monocytes
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary 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.
 
Overall design Transcriptome profiling by mRNA sequencing from CD14+ human monocytes that were differentiated with M-CSF, and then stimulated without or with IFNg treatment for 24h.
 
Contributor(s) McCann KJ, Christensen S, McGuire PJ, Myles IA, Zerbe CS, Li P, Sukumar G, Dalgard CL, Leonard WJ, McCormick BA, Holland SM
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Submission date Jun 10, 2021
Last update date Jan 02, 2022
Contact name Peng Li
E-mail(s) peng.li@nih.gov
Organization name NIH
Department NHLBI
Lab LMI
Street address 9000 Rockville Pike
City Bethesda
State/province MD
ZIP/Postal code 20892
Country USA
 
Platforms (1)
GPL21290 Illumina HiSeq 3000 (Homo sapiens)
Samples (8)
GSM5369059 media-24-ND1
GSM5369060 IFNg-24-ND1
GSM5369061 media-24-ND2
Relations
BioProject PRJNA736708
SRA SRP323592

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Supplementary file Size Download File type/resource
GSE176562_RAW.tar 7.2 Mb (http)(custom) TAR (of RPKM)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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