Extracellular Nicotinamide Phosphoribosyltransferase (eNAMPT) boosts IFNγ-induced macrophage polarization
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ABSTRACT:
PROVIDER: PRJNA781578 | ENA |
REPOSITORIES: ENA
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Project description:Nicotinamide phosphoribosyltransferase (NAMPT), alongside being a crucial enzyme to synthesize NAD in cells, has also been shown to be a secreted protein (eNAMPT). In this respect, this protein is found increased in plasma of cancer patients as well as in patients suffering from immune-mediated disorders and preclinical models have demonstrated that it is involved in their pathogenesis (e.g. (inflammatory bowel disease). In the present contribution, we evaluated the effect of this protein on macrophages performing a comprehensive RNAseq analysis, coupled to functional assays. Using peritoneal exudate cells (PECs), we now report that eNAMPT has chemoattractive and M1-skewing properties in macrophages and this holds true also in human monocyte-derived macrophages. Furthermore, we report that this protein is able to boost the responses to IFNγ, and this is likely to be mediated by STAT1-STAT3-activation. Importantly, IFNγ triggers the upregulation and secretion of eNAMPT, thereby providing evidence of a positive feedback loop upon cytokine activation. Last, we report that these phenomena are not a result of TLR4 activation, the only eNAMPT receptor that has been recognised until now, prompting the knowledge that other receptors may be involved.
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2021-11-04 | PXD017170 | Pride
Project description:Nicotinamide phosphoribosyltransferase (NAMPT) is a key intracellular enzyme that particulates in NAD homeostasis but is also a released cytokine (eNAMPT) that is found elevated in inflammatory conditions and in cancer. Given that in breast cancer patients, eNAMPT has been found elevated and its levels correlate with prognosis and staging, we set to investigate the effect of its neutralization with a specific monoclonal antibody. Neutralization of eNAMPT with C269 led to a decreased tumour size and reduced number of metastases. RNAseq and functional assays showed that eNAMPT controlled the PD-L1/PD-1 axis and its neutralization led to a restoration of antitumoural immune responses. These studies are highly consistent with eNAMPT as a novel immunotherapeutic target for triple negative breast cancer.
2023-01-30 | GSE223539 | GEO
Project description:Through integration of whole genome CRISPR screening and pan-cancer genetic dependency mapping, we identified nicotinamide phosphoribosyltransferase (NAMPT) and nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) as acute myeloid leukemia (AML) dependencies governing NAD+ biosynthesis. While both NAMPT and NMNAT1 were required for AML, we found that the presence of NAD+ precursors bypassed the dependence of AML on NAMPT, but not NMNAT1, pointing to NMNAT1 as a gatekeeper of NAD+ biosynthesis. We provide evidence that reduced nuclear NAD+ upon deletion of NMNAT1 activated p53, which is due to attenuated deacetylation by SIRT6/7 in AML cells. Our findings reveal that NAD+ is a critical metabolic foundation for AML, and NMNAT1 is a novel therapeutic target for this disease.
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Project description:Type 2 diabetes (T2D) has become an epidemic in our modern lifestyle, likely due to calorie-rich diets overwhelming our adaptive metabolic pathways. One such pathway is mediated by nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in mammalian NAD+ biosynthesis, and the NAD+-dependent protein deacetylase SIRT1. Here we show that NAMPT-mediated NAD+ biosynthesis is severely compromised in metabolic organs by high-fat diet (HFD). Strikingly, nicotinamide mononucleotide (NMN), a product of the NAMPT reaction and a key NAD+ intermediate, ameliorates glucose intolerance by restoring NAD+ levels in HFD-induced T2D mice. NMN also enhances hepatic insulin sensitivity and restores gene expression related to oxidative stress, inflammatory response, and circadian rhythm, partly through SIRT1 activation. Furthermore, NAD+ and NAMPT levels show significant decreases in multiple organs during aging, and NMN improves glucose intolerance and lipid profiles in age-induced T2D mice. These findings provide critical insights into a novel intervention against diet- and age-induced T2D. 4 regular chow fed mice (RC1-4) vs 4 high-fat diet fed (HFD) (HFD1a-4a) mice were analyzed on one chip (Chip-A). 4 HFD mice (HFD1b-4b) vs 4 HFD-NMN treated mice (NMN1-4) were examined on the other chip (Chip-B).
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Project description:The cytokine IFNγ differentially impacts on tumors upon immune checkpoint blockade (ICB). Despite our understanding of downstream signaling events, less is known about 36 regulation of its receptor (IFNγ-R1). With an unbiased genome-wide CRISPR/Cas9 screen for critical regulators of IFNγ-R1 cell surface abundance, we identified STUB1 as an E3 ubiquitin ligase for IFNγ-R1 in complex with its signal-relaying kinase JAK1. STUB1 mediates ubiquitination-dependent proteasomal degradation of IFNγ-R1/JAK1 complex through IFNγ-R1K285 and JAK1K249. Conversely, STUB1 inactivation amplifies IFNγ signaling, sensitizing tumor cells to cytotoxic T cells in vitro. This was corroborated by an anticorrelation between STUB1 expression and IFNγ response in ICB-treated patients. Consistent with the context-dependent effects of IFNγ in vivo, anti-PD-1 response was increased in heterogenous tumors comprising both wildtype and STUB1-deficient cells but not full STUB1 knockout tumors. These results uncover STUB1 as a critical regulator of IFNγ-R1, and highlight the context-dependency of STUB1-regulated IFNγ signaling for ICB outcome.
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Project description:Macrophages polarize towards different subpopulations with distinct and partly antagonistic functions in various diseases. IFNγ/LPS-polarized M1-type macrophages can have antiangiogenic activity, whereas IL-4-induced M2-type macrophages can be proangiogenic and profibrotic. Therapeutic strategies to inhibit M2-type polarization while promoting M1-type polarization could serve to inhibit pathological angiogenesis and fibrosis. Here, by combining global quantitative time-course proteomics and phosphoproteomics with a small-molecule inhibitor screen we identify signaling events that promote specifically IL-4-induced and not IFNγ/LPS-induced macrophage polarization and found that the MEK inhibitor trametinib and the HDAC inhibitor panobinostat potently prevent M2-type macrophage polarization without inhibiting M1-type polarization. In contrast, selective B-Raf inhibition promotes M2-type polarization. Trametinib and panobinostat also blocked M2-type macrophage polarization and concomitantly angiogenesis and fibrosis in models of wound healing and neovascular age-related macular degeneration in vivo. Thus, these pharmacologic inhibitors could be utilized therapeutically to selectively block IL4-induced macrophage polarization and reduce pathologic angiogenesis and fibrosis.
2021-10-16 | GSE154345 | GEO
Project description:Macrophages polarize towards different subpopulations with distinct and partly antagonistic functions in various diseases. IFNγ/LPS-polarized M1-type macrophages can have antiangiogenic activity, whereas IL-4-induced M2-type macrophages can be proangiogenic and profibrotic. Therapeutic strategies to inhibit M2-type polarization while promoting M1-type polarization could serve to inhibit pathological angiogenesis and fibrosis. Here, by combining global quantitative time-course proteomics and phosphoproteomics with a small-molecule inhibitor screen we identify signaling events that promote specifically IL-4-induced and not IFNγ/LPS-induced macrophage polarization and found that the MEK inhibitor trametinib and the HDAC inhibitor panobinostat potently prevent M2-type macrophage polarization without inhibiting M1-type polarization. In contrast, selective B-Raf inhibition promotes M2-type polarization. Trametinib and panobinostat also blocked M2-type macrophage polarization and concomitantly angiogenesis and fibrosis in models of wound healing and neovascular age-related macular degeneration in vivo. Thus, these pharmacologic inhibitors could be utilized therapeutically to selectively block IL4-induced macrophage polarization and reduce pathologic angiogenesis and fibrosis.
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