Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Pancreatology. 2021 Aug;21(5):870-883. doi: 10.1016/j.pan.2021.03.011. Epub 2021 Mar 25.
BACKGROUND & OBJECTIVES: Acute pancreatitis is a common inflammatory disorder of the exocrine pancreas with no specific therapy. Intracellular nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in nicotinamide adenine dinucleotide (NAD) salvage pathway, is involved in many inflammatory disorders. In this study, we investigated the role of NAMPT in experimental acute pancreatitis.
Acute pancreatitis was induced in mice using three disparate models: (1) caerulein hyperstimulation, (2) ethanol plus palmitoleic acid, and (3) retrograde biliopancreatic ductal infusion of sodium taurocholate. The NAMPT inhibitor FK866 and NAMPT downstream product nicotinamide mononucleotide (NMN) was administered. Serum and pancreas were collected and analyzed biochemically and histologically. Bone marrow derived macrophages were isolated, cultured with cytokines or pancreatic acini, then analyzed by quantitative PCR and non-targeted metabolomics.
The levels of pancreatic NAMPT and NAD were down-regulated upon acute pancreatitis. NAMPT inhibitor FK866 suppressed M1 macrophage polarization while NMN boosted it. In co-culture of macrophages with acinar cells, inhibition of NAMPT prevented M1-like macrophage differentiation induced by injured pancreatic acini. The injured pancreatic acinar milieu induced a unique metabolic signature linked to macrophage polarization, and inhibition of NAMPT reversed these metabolites changes. Furthermore, NMN supplementation aggravated caerulein hyperstimulation pancreatitis and alcoholic pancreatitis, and inhibition of NAMPT protected against caerulein hyperstimulation, alcoholic and biliary acute pancreatitis and reducing pancreatic macrophage infiltration in vivo.
NAMPT inhibition protects against acute pancreatitis via preventing M1 macrophage polarization and restoring the metabolites related to macrophage polarization and that NAMPT could be a promising therapeutic target for acute pancreatitis.
急性胰腺炎是一种常见的胰腺外分泌炎症性疾病，目前尚无特异性治疗方法。细胞内烟酰胺磷酸核糖转移酶（NAMPT）是烟酰胺腺嘌呤二核苷酸（NAD）补救途径的限速酶，参与多种炎症性疾病。本研究旨在探讨 NAMPT 在实验性急性胰腺炎中的作用。
采用三种不同的模型诱导小鼠急性胰腺炎：（1）蛙皮素过度刺激；（2）乙醇加棕榈油酸；（3）逆行胆胰管内注入牛磺胆酸钠。给予 NAMPT 抑制剂 FK866 和 NAMPT 下游产物烟酰胺单核苷酸（NMN）。收集血清和胰腺进行生化和组织学分析。分离骨髓来源的巨噬细胞，用细胞因子或胰腺腺泡培养，然后进行定量 PCR 和非靶向代谢组学分析。
急性胰腺炎时胰腺 NAMPT 和 NAD 水平下调。NAMPT 抑制剂 FK866 抑制 M1 巨噬细胞极化，而 NMN 则促进其极化。在巨噬细胞与腺泡细胞共培养中，抑制 NAMPT 可阻止受损胰腺腺泡诱导的 M1 样巨噬细胞分化。受损的胰腺腺泡微环境诱导出一种与巨噬细胞极化相关的独特代谢特征，而抑制 NAMPT 可逆转这些代谢物的变化。此外，NMN 补充加重了蛙皮素诱导的胰腺炎和酒精性胰腺炎，而抑制 NAMPT 可保护免受蛙皮素诱导的、酒精性和胆源性急性胰腺炎，并减少体内胰腺巨噬细胞浸润。
NAMPT 抑制通过防止 M1 巨噬细胞极化和恢复与巨噬细胞极化相关的代谢物来保护急性胰腺炎，并且 NAMPT 可能是急性胰腺炎有希望的治疗靶点。
