Objective Nicotinamide phosphoribosyltransferase (NAMPT, also referred to as pre-B cell colony-enhancing factor or visfatin) is critically required for the maintenance of cellular nicotinamide adenine dinucleotide (NAD) supply catalysing the rate-limiting step of the NAD salvage pathway. NAMPT is strongly upregulated in inflammation including IBD and counteracts an increased cellular NAD turnover mediated by NAD-depleting enzymes. These constitute an important mechanistic link between inflammatory, metabolic and transcriptional pathways and NAD metabolism. Design We investigated the impact of NAMPT inhibition by the small-molecule inhibitor FK866 in the dextran sulfate sodium (DSS) model of colitis and the azoxymethane/DSS model of colitis-associated cancer. The impact of NAD depletion on differentiation of mouse and human primary monocytes/macrophages was studied in vitro. Finally, we tested the efficacy of FK866 compared with dexamethasone and infliximab in lamina propria mononuclear cells (LPMNC) isolated from patients with IBD. Results FK866 ameliorated DSS-induced colitis and suppressed inflammation-associated tumorigenesis in mice. FK866 potently inhibited NAMPT activity as demonstrated by reduced mucosal NAD, resulting in reduced abundances and activities of NAD-dependent enzymes including PARP1, Sirt6 and CD38, reduced nuclear factor kappa B activation, and decreased cellular infiltration by inflammatory monocytes, macrophages and activated T cells. Remarkably, FK866 effectively supressed cytokine release from LPMNCs of patients with IBD. As FK866 was also effective in Rag1−⁄− mice, we mechanistically linked FK866 treatment with altered monocyte/macrophage biology and skewed macrophage polarisation by reducing CD86, CD38, MHC-II and interleukin (IL)-6 and promoting CD206, Egr2 and IL-10. Conclusion Our data emphasise the importance of NAD immunometabolism for mucosal immunity and highlight FK866-mediated NAMPT blockade as a promising therapeutic approach in acute intestinal inflammation.

中文翻译：

---

NAD代谢促进人和小鼠肠道炎症

目的 烟酰胺磷酸核糖基转移酶（NAMPT，也称为前 B 细胞集落增强因子或内脂素）对于维持细胞烟酰胺腺嘌呤二核苷酸 (NAD) 供应至关重要，催化 NAD 补救途径的限速步骤。NAMPT 在炎症包括 IBD 中被强烈上调，并抵消由 NAD 消耗酶介导的细胞 NAD 周转增加。这些构成了炎症、代谢和转录途径与 NAD 代谢之间的重要机制联系。设计 我们研究了小分子抑制剂 FK866 抑制 NAMPT 在结肠炎的葡聚糖硫酸钠 (DSS) 模型和结肠炎相关癌症的偶氮甲烷/DSS 模型中的影响。在体外研究了 NAD 消耗对小鼠和人类原代单核细胞/巨噬细胞分化的影响。最后，我们测试了 FK866 与地塞米松和英夫利昔单抗在 IBD 患者分离的固有层单核细胞 (LPMNC) 中的疗效。结果 FK866 在小鼠中改善了 DSS 诱导的结肠炎并抑制了炎症相关的肿瘤发生。FK866 有效抑制 NAMPT 活性，如粘膜 NAD 减少所证明，导致 NAD 依赖性酶（包括 PARP1、Sirt6 和 CD38）的丰度和活性降低，核因子 kappa B 活化减少，以及炎症单核细胞、巨噬细胞和活化 T 细胞的细胞浸润减少. 值得注意的是，FK866 有效抑制了 IBD 患者 LPMNCs 的细胞因子释放。由于 FK866 对 Rag1−⁄− 小鼠也有效，我们通过减少 CD86、CD38、MHC-II 和白细胞介素 (IL)-6 并促进 CD206、Egr2 和 IL-10，机械地将 FK866 治疗与改变的单核细胞/巨噬细胞生物学联系起来，并扭曲巨噬细胞极化。结论我们的数据强调了 NAD 免疫代谢对粘膜免疫的重要性，并强调 FK866 介导的 NAMPT 阻断是一种有前途的急性肠道炎症治疗方法。