Colombo Giorgia, Travelli Cristina, Porta Chiara, Genazzani Armando A
Department of Pharmaceutical Sciences, University of Eastern Piedmont, A. Avogadro, 28100 Novara, Italy.
Department of Drug Sciences, Università degli Studi di Pavia, 27100 Pavia, Italy.
iScience. 2022 Mar 23;25(4):104147. doi: 10.1016/j.isci.2022.104147. eCollection 2022 Apr 15.
Nicotinamide phosphoribosyltransferase (NAMPT), alongside being a crucial enzyme in NAD synthesis, has been shown to be a secreted protein (eNAMPT), whose levels are increased in patients affected by immune-mediated disorders. Accordingly, preclinical studies have highlighted that eNAMPT participates in the pathogenesis of several inflammatory diseases. Herein, we analyzed the effects of eNAMPT on macrophage-driven inflammation. RNAseq analysis of peritoneal macrophages (PECs) demonstrates that eNAMPT triggers an M1-skewed transcriptional program, and this effect is not dependent on the enzymatic activity. Noteworthy, both in PECs and in human monocyte-derived macrophages, eNAMPT selectively boosts IFNγ-driven transcriptional activation STAT1/3 phosphorylation. Importantly, the secretion of eNAMPT promotes the chemotactic recruitment of myeloid cells, therefore providing a potential positive feedback loop to foster inflammation. Last, we report that these events are independent of the activation of TLR4, the only eNAMPT receptor that has hitherto been recognized, prompting the knowledge that other receptors are involved.
烟酰胺磷酸核糖转移酶（NAMPT）不仅是NAD合成中的关键酶，还被证明是一种分泌蛋白（eNAMPT），在免疫介导疾病患者中其水平会升高。因此，临床前研究强调eNAMPT参与了多种炎症性疾病的发病机制。在此，我们分析了eNAMPT对巨噬细胞驱动的炎症的影响。对腹膜巨噬细胞（PEC）的RNAseq分析表明，eNAMPT触发了偏向M1的转录程序，且这种效应不依赖于酶活性。值得注意的是，在PEC和人单核细胞衍生的巨噬细胞中，eNAMPT都选择性地增强了IFNγ驱动的转录激活——STAT1/3磷酸化。重要的是，eNAMPT的分泌促进了髓样细胞的趋化募集，因此提供了一个潜在的正反馈回路来促进炎症。最后，我们报告这些事件独立于TLR4的激活，TLR4是迄今为止唯一被认可的eNAMPT受体，这促使人们认识到还有其他受体参与其中。
