Extracellular Nicotinamide Phosphoribosyltransferase (eNAMPT) boosts IFN?-induced macrophage polarization

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 IFN?, and this is likely to be mediated by STAT1-STAT3-activation. Importantly, IFN? 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. Overall design: We used 5 replicates of 4 samples (CTRL, eNAMPT, IFN? and IFN?+eNAMPT treated) using Illumina NextSeq 500