NAMPT mitigates colitis severity by supporting redox-sensitive activation of phagocytosis in inflammatory macrophages.

Abstract

Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the nicotinamide adenine dinucleotide (NAD+) salvage pathway and plays a crucial role in the maintenance of the NAD+ pool during inflammation. Considering that macrophages are essential for tissue homeostasis and inflammation, we sought to examine the functional impact of NAMPT in inflammatory macrophages, particularly in the context of inflammatory bowel disease (IBD). In this study, we show that mice with NAMPT deletion within the myeloid compartment (Namptf/fLysMCre+/-, Nampt mKO) have more pronounced colitis with lower survival rates, as well as numerous uncleared apoptotic corpses within the mucosal layer. Nampt-deficient macrophages exhibit reduced phagocytic activity due to insufficient NAD+ abundance, which is required to produce NADPH for the oxidative burst. Nicotinamide mononucleotide (NMN) treatment rescues NADPH levels in Nampt mKO macrophages and sustains superoxide generation via NADPH oxidase. Consequently, Nampt mKO mice fail to clear dead cells during tissue repair, leading to substantially prolonged chronic colitis. Moreover, systemic administration of NMN, to supply NAD+, effectively suppresses the disease severity of DSS-induced colitis. Collectively, our findings suggest that activation of the NAMPT-dependent NAD+ biosynthetic pathway, via NMN administration, is a potential therapeutic strategy for managing inflammatory diseases.

• Authors: Sun Mi Hong, A-Yeon Lee, Sung-Min Hwang, Yu-Jin Ha, Moo-Jin Kim, Seongki Min, Won Hwang, Gyesoon Yoon, So Mee Kwon, Hyun Goo Woo, Hee-Hoon Kim, Won-Il Jeong, Han-Ming Shen, Sin-Hyeog Im, Dakeun Lee, You-Sun Kim
• Journal: Redox biology (Redox Biol) Vol. 50 Pg. 102237 (04 2022) ISSN: 2213-2317 [Electronic] Netherlands
• PMID: 35063804 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Cytokines
• NAD
• Nicotinamide Phosphoribosyltransferase
• nicotinamide phosphoribosyltransferase, mouse

Topics

• Animals
• Colitis (chemically induced, metabolism)
• Cytokines (metabolism)
• Macrophages (metabolism)
• Mice
• NAD (metabolism)
• Nicotinamide Phosphoribosyltransferase (genetics, metabolism)
• Oxidation-Reduction
• Phagocytosis