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Extracellular Nicotinamide Phosphoribosyltransferase (eNAMPT) boosts IFNγ-induced macrophage polarization

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE189104 | GEO | 2021/11/20

REPOSITORIES: GEO

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Project description:Interferon (IFN)γ and interleukin (IL)-4 are central regulators of T helper 1 (Th1) and T helper 2 (Th2) immune responses, respectively. Both cytokines have a major impact on macrophage phenotypes: IFNγ–priming and subsequent TLR4 activation induces so called classically activated macrophages that are characterized by pronounced pro-inflammatory responses, whereas IL-4–treated macrophages, commonly called alternatively activated, are known to develop enhanced capacity for endocytosis, antigen presentation, and tissue repair and are generally considered anti-inflammatory. Considering IL-4 as priming rather than activating stimulus, we now compared the TLR4–dependent global gene activation program in IFNγ– versus IL-4–pretreated mouse macrophages, which has rarely been studied so far. Although both cytokines frequently induced opposing effects on gene transcription, the subsequent activation of bone marrow-derived macrophages by lipopolysaccharide (LPS) produced a strong, priming dependent pro-inflammatory response in both macrophage types. For example, the production of key pro-inflammatory cytokines IL-6 and IL-12 was significantly higher in IL-4– versus IFNγ–primed macrophages and several cytokine genes, including Il19, Ccl17, Ccl22, Ccl24 and Cxcl5, were preferentially induced in alternatively primed and LPS activated mouse macrophages. In a subset of genes, including IL12a, IFNγ priming was actually found to suppress LPS–induced gene expression in a Stat1–dependent manner. Our data suggest that IL-4–priming is not per se anti-inflammatory but generates a macrophage that is “tissue protective” but still capable of mounting a strong inflammatory response after TLR4–dependent activation. Keywords: Gene expression profiling Gene expression was investigated in mouse bone marrow-derived macrophages (BMM). On day 7, BMM were stimulated with either IL-4 or IFNγ overnight (18h in total). LPS treatment was performed in primed and unprimed macrophages 4 h prior to harvesting. At least three independent experiments were performed for each condition.

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Extracellular Nicotinamide Phosphoribosyltransferase (eNAMPT) boosts IFNγ-induced macrophage polarization

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