Inhibition of nicotinamide phosphoribosyltransferase protects against acute pancreatitis via modulating macrophage polarization and its related metabolites

Yan He; Juanjuan Dai; Mengya Niu; Bin Li; Congying Chen; Mingjie Jiang; Zengkai Wu; Jingpiao Bao; Xiuli Zhang; Liang Li; Sohail Z Husain; Guoyong Hu; Li Wen

doi:10.1016/j.pan.2021.03.011

Inhibition of nicotinamide phosphoribosyltransferase protects against acute pancreatitis via modulating macrophage polarization and its related metabolites

Pancreatology. 2021 Aug;21(5):870-883. doi: 10.1016/j.pan.2021.03.011. Epub 2021 Mar 25.

Authors

Yan He¹, Juanjuan Dai¹, Mengya Niu¹, Bin Li¹, Congying Chen¹, Mingjie Jiang², Zengkai Wu¹, Jingpiao Bao¹, Xiuli Zhang¹, Liang Li¹, Sohail Z Husain³, Guoyong Hu⁴, Li Wen⁵

Affiliations

¹ 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.
² 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.
³ Division of Pediatric Gastroenterology, Department of Pediatrics, Stanford University, Palo Alto, CA, United States.
⁴ 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. Electronic address: huguoyongsh@sina.com.
⁵ 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. Electronic address: wenli7007@gmail.com.

PMID: 33810973
DOI: 10.1016/j.pan.2021.03.011

Abstract

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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: FK866; Macrophage polarization; Metabolites; NAMPT; NMN.

MeSH terms

Acute Disease
Animals
Ceruletide
Cytokines
Macrophages
Mice
NAD
Nicotinamide Mononucleotide
Nicotinamide Phosphoribosyltransferase*
Pancreatitis* / chemically induced
Sirtuin 1

Substances

Cytokines
NAD
Nicotinamide Mononucleotide
Ceruletide
Nicotinamide Phosphoribosyltransferase
Sirtuin 1